Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals

ABSTRACT

Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals  
     The invention relates to arylcycloalkyl-substituted alkanoic acid derivatives and to their physiologically acceptable salts and physiologically functional derivatives.  
     What is described are compounds of the formula I,  
                 
 
     in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparation. The compounds are suitable, for example, for the treatment and/or prevention of disorders of the fatty acid metabolism and glucose utilization disorders and also disorders in which insulin resistance is involved.

DESCRIPTION

[0001] The invention relates to arylcycloalkyl-substituted alkanoic acidderivatives and to their physiologically acceptable salts andphysiologically functional derivatives.

[0002] Compounds of a similar structure have already been described inthe prior art for the treatment of hyperlipidemia and diabetes (WO2000/64876).

[0003] It was an object of the invention to provide compounds whichpermit a therapeutically exploitable modulation of the lipid and/orcarbohydrate metabolism and are thus suitable for the prevention and/ortreatment of disorders such as type 2 diabetes and atherosclerosis andtheir multifarious sequelae.

[0004] Surprisingly, a number of compounds which modulate the activityof PPAR receptors have been found. The compounds are particularlysuitable for activating PPARalpha and PPARgamma, where the extent of therelative activation may vary, depending on the compounds.

[0005] The invention thus relates to compounds of the formula I

[0006] wherein:

[0007] Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl,wherein one or more carbon atoms of said (C3-C8)-cycloalkanediyl and(C3-C8)-cycloalkenediyl groups are optionally replaced by oxygen atoms;

[0008] R1, R2 are each independently H, F, Cl, Br, CF₃, OCF₃,(C1-C6)-alkyl, O-(C1-C6)-alkyl, SCF₃, SF₅, OCF₂-CHF₂, (C6-C10)-aryl,(C6-C10)-aryloxy, OH or NO₂; or

[0009] R1and R2, taken together with the atoms of the phenyl, pyridine,1-H-pyrrole, thiophene or furan rings to which they are attached, form afused, partially saturated or unsaturated, bicyclic (C6-C10)-aryl or(C5-C11)-heteroaryl group;

[0010] R3 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl,(C1-C3)-alkyl-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkyl-phenyl,(C5-C6)-heteroaryl, (C1-C3)-alkyl-(C5-C6)-heteroaryl or (C1-C3)-alkylwhich is fully or partially substituted by F;

[0011] W is CH orN, if o =1;

[0012] W is O, S or NR9,if o=0;

[0013] X is (C1-C6)-alkanediyl, wherein one or more carbon atoms of said(C1-C6)-alkanediyl group are optionally replaced by oxygen atoms;

[0014] Y1 is O;

[0015] Y2 is CR12R13, SO or SO₂;

[0016] n is 0, 1 or 2;

[0017] R4 is H, F or (C1-C6)-alkyl;

[0018] R5 is H, F or (C1-C6)-alkyl;

[0019] R6 is H or (C1-C6)-alkyl; or is F if n is not 0;

[0020] R7 is H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,(C3-C8)-cycloalkyl, phenyl, (C5-C11)-heteroaryl, O-(C3-C8)-cycloalkyl orO-phenyl,

[0021] wherein said (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl and O-phenyl groups are optionally substituted byOH, NR10R11, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl, O-phenyl or O-(C5-C11)-heteroaryl, and

[0022] said (C3-C8)-cycloalkyl, phenyl and (C5-C11)-heteroaryl groupsare optionally substituted by OH, NR10R11, O-(C1-C6)-alkyl,O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl, O-(C3-C8)-cycloalkyl, O-phenyl,O-(C5-C11)-heteroaryl or (C1-C6)-alkyl,

[0023] wherein said (C1-C6)-alkyl substituent is optionally substitutedby F (fully or partially) or O-(C1-C6)-alkyl,

[0024] wherein said O-(C1-C6)-alkyl substituent is optionallysubstituted by F (fully or partially), Cl, Br, I, OH, NR10R11,CO-(C1-C6)-alkyl, CO-(C6-C10)-aryl, CO-(C1-C6)-alkyl-(C6-C10)-aryl,CO-(C5-C11)-heteroaryl, C(O)-O-(C1-C6)-alkyl,C(O)-O-(C1-C6)-alkyl-(C6-C10)-aryl, C(O)-O-(C6-C10)-aryl,C(O)-O-(C5-C11)-heteroaryl, SO₂-(C1-C6)-alkyl,SO₂-(C1-C6)-alkyl-(C6-C10)-aryl, SO₂-(C1-C6)-alkyl-SO₂-(C1-C6)-alkyl,SO₂-(C6-C10)-aryl, SO₂-(C5-C11)-heteroaryl; or

[0025] R6 and R7, together with the carbon atom to which they areattached, form a (C3-C8)-cycloalkyl group;

[0026] R8 is H or (C1-C6)-alkyl;

[0027] R9 is H or (C1-C6)-alkyl which is optionally substituted byphenyl;

[0028] R10 is H or (C1-C6)-alkyl which is optionally substituted byphenyl;

[0029] R11 is H or (C1-C6)-alkyl which is optionally substituted byphenyl;

[0030] R12 is H or (C1-C6)-alkyl;

[0031] R13 is H or (C1-C6)-alkyl;

[0032] and pharmaceutically acceptable salts thereof.

[0033] Preference is given to compounds of the formula I wherein:

[0034] Ring A is (C₃-C₈)-cycloalkanediyl or (C₃-C₈)-cycloalkenediyl,wherein one or more of the carbon atoms in said (C₃-C₈)-cycloalkanediylor (C₃-C₈)-cycloalkenediyl groups are optionally replaced by oxygenatoms;

[0035] X is (C1-C6)-alkanediyl, wherein the C1 or C2 carbon atom (withrespect to Ring A) in said (C1-C6)-alkanediyl group is optionallyreplaced by an oxygen atom;

[0036] and pharmaceutically acceptable salts thereof.

[0037] Particular preference is given to compounds of the formula I inwhich one or more radicals are as defined below:

[0038] Ring A is cyclohexane-1,3-diyl;

[0039] R1 is F, Br, CF₃, OCF₃, (C1-C6)-alkyl, O-(C1-C6)-alkyl or phenyl;

[0040] R1 is located in a position meta- or para- to the carbon atom ofthe phenyl ring that is attached to the oxazol ring;

[0041] R2 is hydrogen; or

[0042] R1 and R2, taken together with the phenyl ring to which they areattached, form naphthyl;

[0043] R3 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl,(C1-C3)-alkyl-(C5-C6)-cycloalkyl, phenyl or (C1-C3)-alkyl-phenyl;

[0044] W is CH, if o=1;

[0045] X is CH₂-O or CH₂-O-CH₂;

[0046] n is0;

[0047] R6 is H or (C1-C6)-alkyl;

[0048] R7 is H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,(C3-C8)-cycloalkyl, phenyl, O-(C3-C8)-cycloalkyl, O-phenyl,(C5-C11)-heteroaryl,

[0049] wherein said (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl, and O-phenyl groups are optionally substituted byOH, NR1 0R1 1, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl, O-phenyl or O-(C5-C11 )-heteroaryl, and

[0050] said (C3-C8)-cycloalkyl, phenyl and (C5-C11)-heteroaryl groupsare optionally substituted by OH, NR10R11, O-(C1-C6)-alkyl,O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl, O-(C3-C8)-cycloalkyl, O-phenyl orO-(C5-C11)-heteroaryl or (Cl -C6)-alkyl,

[0051] wherein said (C1-C6)-alkyl substituent is optionally substitutedby F (fully or partially) or O-(C1-C6)-alkyl,

[0052] wherein said O-(C1-C6)-alkyl substituent is optionallysubstituted by F (fully or partially), Cl, Br, I, OH, NR10R11; or

[0053] R6 and R7, taken together with the carbon atom to which they areattached, form (C3-C6)-cycloalkyl, in particular cyclopentyl;

[0054] R10 and R11 are each independently H or (C1-C6)-alkyl;

[0055] R12 and R13 are hydrogen.

[0056] Particular preference is furthermore given to the compounds ofthe formula I in which

[0057] R7 is H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,(C3-C8)-cycloalkyl, phenyl or (C5-C 11)-heteroaryl,

[0058] wherein said (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl and(C3-C8)-cycloalkyl groups are optionally substituted by NR10R11,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl, O-phenyl or O-(C5-C11)-heteroaryl,

[0059] and said phenyl and (C5-C11)-heteroaryl groups are optionallysubstituted by NR10R11, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl,O-(C2-C6)-alkynyl, O-(C3-C8)-cycloalkyl, O-phenyl, O-(C5-C11)-heteroarylor (C1-C6)-alkyl,

[0060] wherein said (Cl-C6)-alkyl substituent is optionally substitutedby F (fully or partially) or O-(C1-C6)-alkyl,

[0061] wherein said O-(C1-C6)-alkyl substituent is optionallysubstituted by F (fully or partially), Cl or NR10R11;

[0062] and pharmaceutically acceptable salts thereof.

[0063] Very particular preference is given to the compounds of theformula I

[0064] wherein

[0065] Ring A is cis-cyclohexane-1,3-diyl;

[0066] R1, R2 are each independently H, F, CF3, (C1-C6)-alkyl,O-(C1-C6)-alkyl or phenyl, or

[0067] R1 and R2, taken together with the phenyl ring to which they areattached, form naphthyl;

[0068] R3 is (C1-C6)-alkyl;

[0069] W is CH, if o=1;

[0070] X is (CH2)O or CH2-O—CH2;

[0071] Y1 is 0;

[0072] Y2 is CH2;

[0073] n is 0 or 1;

[0074] R4 is H;

[0075] R5 is H;

[0076] R6 is H;

[0077] R7 is H, (C1-C6)-alkyl, O-(C1-C6)-alkyl,(C1-C6)-alkyl-O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl orCH2NR10R11,

[0078] wherein said (C1-C6)-alkyl, O-(C1-C6)-alkyl and O-(C2-C6)-alkenylgroups are optionally substituted by phenyl or (C5-C6)-heteroaryl,

[0079] wherein said phenyl and (C5-C6)-heteroaryl substituents areoptionally substituted by (C1-C6)-alkyl, O-(C1-C6)-alkyl or CF3; or

[0080] R6 and R7, together with the carbon atom to which they areattached, form (C3-C6)-cycloalkyl;

[0081] R8 is H;

[0082] R10 is (C1-C6)-alkyl;

[0083] R11 is (C1-C6)-alkyl which is substituted by phenyl;

[0084] and pharmaceutically acceptable salts thereof.

[0085] The alkyl radicals in the substituents R1, R2, R3, R4, R5 , R6,R7, R8, R9, R10, R11, R12 and R13 may be either straight-chain orbranched.

[0086] Aryl means an aromatic carbocyclic mono- or bicyclic ring systemwhich comprises 6 to 10 atoms in the ring or rings.

[0087] Heteroaryl is a mono- or bicyclic aromatic ring system having 4to 11 ring members, in which at least one atom in the ring system is aheteroatom from the series N, O and S.

[0088] The compounds of the formula I comprise at least two centers ofasymmetry and may comprise more in addition. The compounds of theformula I may therefore exist in the form of their racemates, racemicmixtures, pure enantiomers, diastereomers and mixtures of diastereomers.The present invention encompasses all these isomeric forms of thecompounds of the formula I. These isomeric forms can be obtained byknown methods even if not specifically described in some cases.

[0089] Pharmaceutically acceptable salts are, because their solubilityin water is greater than that of the initial or basic compounds,particularly suitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

[0090] Salts with a pharmaceutically unacceptable anion such as, forexample, trifluoroacetate likewise belong within the framework of theinvention as useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

[0091] As used herein, the following definitions apply:

[0092] “Patient” means a warm blooded animal, such as for example rat,mice, dogs, cats, guinea pigs, and primates such as humans.

[0093] “Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orto prevent or slow the appearance of symptoms of the named disorder orcondition.

[0094] “Therapeutically effective amount” means a quantity of thecompound which is effective in treating the named disorder or condition.

[0095] “Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

[0096] The term “physiologically functional derivative” used hereinrefers to any physiologically tolerated derivative of a compound of theformula I of the invention, for example an ester, which onadministration to a mammal such as, for example, a human is able to form(directly or indirectly) a compound of the formula I or an activemetabolite thereof.

[0097] Physiologically functional derivatives also include prodrugs ofthe compounds of the invention, as described, for example, in H. Okadaet al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

[0098] The compounds of the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theinvention belong within the framework of the invention and are a furtheraspect of the invention.

[0099] All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

[0100] Use

[0101] This invention relates further to the use of compounds of theformula I and their pharmaceutical compositions as PPAR ligands. ThePPAR ligands of the invention are suitable as modulators of PPARactivity.

[0102] Peroxisome proliferator-activated receptors (PPAR) aretranscription factors which can be activated by ligands and belong tothe class of nuclear hormone receptors. There are three PPAR isoforms,PPARalpha, PPARgamma and PPARdelta, which are encoded by different genes(Peroxisome proliferator-activated receptor (PPAR): structure,mechanisms of activation and diverse functions: Motojima K, Cell StructFunct. 1993 Oct; 18(5): 267-77).

[0103] Two variants of PPARgamma exist, PPARgamma₁ and gamma₂, which arethe result of alternative use of promoters and differential mRNAsplicing (Vidal-Puig et al. J. Clin. Invest., 97:2553-2561, 1996).Different PPARs have different tissue distribution and modulatedifferent physiological functions. The PPARs play a key role in variousaspects of the regulation of a large number of genes, the products ofwhich genes are directly or indirectly crucially involved in lipid andcarbohydrate metabolism. Thus, for example, PPARalpha receptors play animportant part in the regulation of fatty acid catabolism or lipoproteinmetabolism in the liver, while PPARgamma is crucially involved forexample in regulating adipose cell differentiation. In addition,however, PPARs are also involved in the regulation of many otherphysiological processes, including those which are not directlyconnected with carbohydrate or lipid metabolism. The activity ofdifferent PPARs can be modulated by various fatty acids, fatty acidderivatives and synthetic compounds to varying extents. For relevantreviews about functions, physiological effect and pathophysiology, see:Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson etal. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al.,Recent Prog Horm Res. 2001; 56: 239-63.

[0104] The present invention relates to compounds of the formula Isuitable for modulating the activity of PPARs, especially the activityof PPARalpha and PPARgamma. Depending on the modulation profile, thecompounds of the formula I are suitable for the treatment, control andprophylaxis of the indications described hereinafter, and for a numberof other pharmaceutical applications connected thereto (see, forexample, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; TimothyWilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; StevenKliewer et al., Recent Prog Horm Res. 2001; 56: 239-63; Jean-CharlesFruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease andArteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52;2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARsin health and disease, NATURE, VOL 405, 25 MAY 2000; 421-4; Ines PinedaTorra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and BartStaels: Peroxisome proliferator-activated receptors: fromtranscriptional control to clinical practice, Curr Opin Lipidol 12:2001, 245-254).

[0105] Compounds of this type are particularly suitable for thetreatment and/or prevention of

[0106] 1. disorders of fatty acid metabolism and glucose utilizationdisorders

[0107] disorders in which insulin resistance is involved

[0108] 2. Diabetes mellitus, especially type 2 diabetes, including theprevention of the sequelae associated therewith.

[0109] Particular aspects in this connection are

[0110] hyperglycemia,

[0111] improvement in insulin resistance,

[0112] improvement in glucose tolerance,

[0113] protection of the pancreatic β cells

[0114] prevention of macro- and microvascular disorders

[0115] 3. Dyslipidemias and their sequelae such as, for example,atherosclerosis, coronary heart disease, cerebrovascular disorders etc,especially those (but not restricted thereto) which are characterized byone or more of the following factors:

[0116] high plasma triglyceride concentrations, high postprandial plasmatriglyceride concentrations,

[0117] low HDL cholesterol concentrations

[0118] low ApoA lipoprotein concentrations

[0119] high LDL cholesterol concentrations

[0120] small dense LDL cholesterol particles

[0121] high ApoB lipoprotein concentrations

[0122] 4. Various other conditions which may be associated with themetabolic syndrome, such as:

[0123] obesity (excess weight), including central obesity

[0124] thromboses, hypercoagulable and prothrombotic states (arterialand venous)

[0125] high blood pressure

[0126] heart failure such as, for example (but not restricted thereto),following myocardial infarction, hypertensive heart disease orcardiomyopathy

[0127] 5. Other disorders or conditions in which inflammatory reactionsor cell differentiation may for example be involved are:

[0128] atherosclerosis such as, for example (but not restrictedthereto), coronary sclerosis including angina pectoris or myocardialinfarction, stroke

[0129] vascular restenosis or reocclusion

[0130] chronic inflammatory bowel diseases such as, for example, Crohn'sdisease and ulcerative colitis

[0131] pancreatitis

[0132] other inflammatory states

[0133] retinopathy

[0134] adipose cell tumors

[0135] lipomatous carcinomas such as, for example, liposarcomas

[0136] solid tumors and neoplasms such as, for example (but notrestricted thereto), carcinomas of the gastrointestinal tract, of theliver, of the biliary tract and of the pancreas, endocrine tumors,carcinomas of the lungs, of the kidneys and the urinary tract, of thegenital tract, prostate carcinomas etc

[0137] acute and chronic myeloproliferative disorders and lymphomas

[0138] angiogenesis

[0139] neurodegenerative disorders

[0140] Alzheimer's disease

[0141] multiple sclerosis

[0142] Parkinson's disease

[0143] erythemato-squamous dermatoses such as, for example, psoriasis

[0144] acne vulgaris

[0145] other skin disorders and dermatological conditions which aremodulated by PPAR

[0146] eczemas and neurodermitis

[0147] dermatitis such as, for example, seborrheic dermatitis orphotodermatitis

[0148] keratitis and keratoses such as, for example, seborrheickeratoses, senile keratoses, actinic keratosis, photo-induced keratosesor keratosis follicularis

[0149] keloids and keloid prophylaxis

[0150] warts, including condylomata or condylomata acuminata

[0151] human papilloma viral (HPV) infections such as, for example,venereal papillomata, viral warts such as, for example, molluscumcontagiosum, leukoplakia

[0152] papular dermatoses such as, for example, Lichen planus

[0153] skin cancer such as, for example, basal-cell carcinomas,melanomas or cutaneous T-cell lymphomas

[0154] localized benign epidermal tumors such as, for example,keratoderma, epidermal naevi

[0155] chilblains

[0156] high blood pressure

[0157] syndrome X

[0158] polycystic ovary syndrome (PCOS)

[0159] asthma

[0160] osteoarthritis

[0161] lupus erythematosus (LE) or inflammatory rheumatic disorders suchas, for example, rheumatoid arthritis

[0162] vasculitis

[0163] wasting (cachexia)

[0164] gout

[0165] ischemia/reperfusion syndrome

[0166] acute respiratory distress syndrome (ARDS)

[0167] Formulations

[0168] The amount of a compound of formula I necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.001 mg to 100 mg (typically from 0.01mg to 50 mg) per day and per kilogram of bodyweight, for example 0.1-10mg/kg/day. An intravenous dose may be, for example, in the range from0.001 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, from 0.1 ng to 10 mg,typically from 1 ng to 10 mg, per milliliter. Single doses may contain,for example, from 1 mg to 10 g of the active ingredient. Thus, ampulesfor injections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, capsules or tablets, may contain, for example, from 0.05 to1000 mg, typically from 0.5 to 600 mg. For the therapy of theabovementioned conditions, the compounds of formula I may be used as thecompound itself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

[0169] Pharmaceutical compositions of the invention are those suitablefor oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable mode ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound of formula I used in each case. Coated formulations and coatedslow-release formulations also belong within the framework of theinvention. Preference is given to acid- and gastric juice-resistantformulations. Suitable coatings resistant to gastric juice comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0170] Suitable pharmaceutical preparations for oral administration maybe in the form of separate units such as, for example, capsules,cachets, suckable tablets or tablets, each of which contain a definedamount of the compound of formula I; as powders or granules, as solutionor suspension in an aqueous or nonaqueous liquid; or as an oil-in-wateror water-in-oil emulsion. These compositions may, as already mentioned,be prepared by any suitable pharmaceutical method which includes a stepin which the active ingredient and the carrier (which may consist of oneor more additional ingredients) are brought into contact. Thecompositions are generally produced by uniform and homogeneous mixing ofthe active ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

[0171] Pharmaceutical compositions which are suitable for peroral(sublingual) administration comprise suckable tablets which contain acompound of formula I with a flavoring, normally sucrose and gum arabicor tragacanth, and pastilles which comprise the compound in an inertbase such as gelatin and glycerol or sucrose and gum arabic.

[0172] Pharmaceutical compositions suitable for parenteraladministration comprise preferably sterile aqueous preparations of acompound of formula 1, which are preferably isotonic with the blood ofthe intended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

[0173] Pharmaceutical compositions suitable for rectal administrationare preferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

[0174] Pharmaceutical compositions suitable for topical use on the skinare preferably in the form of ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5to2%.

[0175] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal uses can be in the form of singleplasters which are suitable for long-term close contact with thepatient's epidermis. Such plasters suitably contain the activeingredient in an aqueous solution which is buffered where appropriate,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active ingredient concentration is about 1% to 35%, preferablyabout 3% to 15%. A particular possibility is for the active ingredientto be released by electrotransport or iontophoresis as described, forexample, in Pharmaceutical Research, 2(6): 318 (1986).

[0176] The compounds of the formula I are distinguished by favorableeffects on metabolic disorders. They beneficially influence lipid andsugar metabolism, in particular they lower the triglyceride level andare suitable for the prevention and treatment of type II diabetes andarteriosclerosis and the diverse sequalae thereof.

[0177] Combinations with other medicaments

[0178] The compounds of the invention can be administered alone or incombination with one or more further pharmacologically active substanceswhich have, for example, favorable effects on metabolic disturbances ordisorders frequently associated therewith. Examples of such medicamentsare

[0179] 1. medicaments which lower blood glucose, antidiabetics,

[0180] 2. active ingredients for the treatment of dyslipidemias,

[0181] 3. antiatherosclerotic medicaments,

[0182] 4. antiobesity agents,

[0183] 5. antiinflammatory active ingredients

[0184] 6. active ingredients for the treatment of malignant tumors

[0185] 7. antithrombotic active ingredients

[0186] 8. active ingredients for the treatment of high blood pressure

[0187] 9. active ingredients for the treatment of heart failure and

[0188] 10. active ingredients for the treatment and/or prevention ofcomplications caused by diabetes or associated with diabetes.

[0189] They can be combined with the compounds of the invention of theformula I in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

[0190] Examples which may be mentioned are:

[0191] Antidiabetics

[0192] Suitable antidiabetics are disclosed for example in the RoteListe 2001, chapter 12 or in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001. Antidiabeticsinclude all insulins and insulin derivatives such as, for example,Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins(see U.S. Pat. No. 6,221,633), GLP-1 receptor modulators as described inWO 01/04146 or else, for example, those disclosed in WO 98/08871 of NovoNordisk A/S.

[0193] The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones', thiazolidinediones, glucosidase inhibitors,glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, potassiumchannel openers such as, for example, those disclosed in WO 97/26265 andWO 99/03861, insulin sensitizers, inhibitors of liver enzymes involvedin the stimulation of gluconeogenesis and/or glycogenolysis, modulatorsof glucose uptake, compounds which alter lipid metabolism and lead to achange in the blood lipid composition, compounds which reduce foodintake, PPAR and PXR modulators and active ingredients which act on theATP-dependent potassium channel of the beta cells.

[0194] In one embodiment of the invention, the compounds of the formulaI are administered in combination with insulin.

[0195] In one embodiment of the invention, the compounds of the formulaI are administered in combination with substances which influencehepatic glucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188)

[0196] In one embodiment, the compounds of the formula I areadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glipizide or glimepiride.

[0197] In one embodiment, the compounds of the formula I areadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

[0198] In one embodiment, the compounds of the formula I areadministered in combination with a biguanide such as, for example,mefformin.

[0199] In a further embodiment, the compounds of the formula I areadministered in combination with a meglitinide such as, for example,repaglinide.

[0200] In one embodiment, the compounds of the formula I areadministered in combination with a thiazolidinedione such as, forexample, ciglitazone, pioglitazone, rosiglitazone or the compoundsdisclosed in WO 97/41097 of Dr. Reddy's Research Foundation, inparticular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0201] In one embodiment, the compounds of the formula I areadministered in combination with a DPPIV inhibitor as described, forexample, in WO98/19998, WO 99/61431, WO 99/67278, WO 99/67279,WO01/72290, WO 02/38541, WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021 ((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

[0202] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPARgamma agonist such as, forexample, rosiglitazone, pioglitazone.

[0203] In one embodiment, the compounds of the formula I areadministered in combination with compounds with an inhibitory effect onSGLT-1 and/or 2, as disclosed directly or indirectly for example inPCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.

[0204] In one embodiment, the compounds of the formula I areadministered in combination with an a-glucosidase inhibitor such as, forexample, miglitol or acarbose.

[0205] In one embodiment, the compounds of the formula I areadministered in combination with more than one of the aforementionedcompounds, e.g. in combination with a sulfonylurea and mefformin, asulfonylurea and acarbose, repaglinide and mefformin, insulin and asulfonylurea, insulin and mefformin, insulin and troglitazone, insulinand lovastatin, etc.

[0206] Lipid modulators

[0207] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an HMGCOA reductase inhibitorsuch as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

[0208] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a bile acid reabsorptioninhibitor (see, for example, U.S. Pat. No. 6,245,744, U.S. Pat. No.6,221,897, U.S. Pat. No. 6,277,831, EP 0683 773, EP 0683 774).

[0209] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a polymeric bile acid adsorbentsuch as, for example, cholestyramine, colesevelam.

[0210] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a cholesterol absorptioninhibitor as described for example in WO 0250027, or ezetimibe,tiqueside, pamaqueside.

[0211] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

[0212] In one embodiment, the compounds of the formula I areadministered in combination with bulking agents, preferably insolublebulking agents (see, for example, carob/Caromax® (Zunft H J; et al.,Carob pulp preparation for treatment of hypercholesterolemia, ADVANCESIN THERAPY (2001 September-October), 18(5), 230-6.) Caromax is acarob-containing product from Nutrinova, Nutrition Specialties & FoodIngredients GmbH, Industriepark Hoechst, 65926 Frankfurt/Main)).Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromax® canin this connection also be administered in the form of food productssuch as, for example, in bakery products or muesli bars.

[0213] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a PPARalpha agonist.

[0214] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a mixed PPAR alpha/gamma agonistsuch as, for example, AZ242 (Tesaglitazar,(S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionicacid), BMS 298585(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine)or as described in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169,WO96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO00/64876.

[0215] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

[0216] In one embodiment of the invention, the compounds of the formulaI are administered in combination with nicotinic acid or niacin.

[0217] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a CETP inhibitor, e.g. CP-529,414 (torcetrapib).

[0218] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ACAT inhibitor.

[0219] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an MTP inhibitor such as, forexample, implitapide.

[0220] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an antioxidant.

[0221] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein lipase inhibitor.

[0222] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an ATP citrate lyase inhibitor.

[0223] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a squalene synthetase inhibitor.

[0224] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipoprotein(a) antagonist.

[0225] Antiobesity agents

[0226] In one embodiment of the invention, the compounds of the formulaI are administered in combination with a lipase inhibitor such as, forexample, orlistat.

[0227] In one embodiment, the further active ingredient is fenfluramineor dexfenfluramine.

[0228] In another embodiment, the further active ingredient issibutramine.

[0229] In a further embodiment, the compounds of the formula I areadministered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormoneand Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g.naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl }amidehydrochloride (CGP 71683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists(e.g. 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylureahydrochloride (SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNFagonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin),urocortin agonists, β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulatinghormone) agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotoninreuptake inhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),bombesin agonists, galanin antagonists, growth hormone (e.g. humangrowth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tertiary butyl ester (WO 01/85695)), TRH agonists (see, forexample, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO00/78312), RXR modulators or TR-β agonists.

[0230] In one embodiment of the invention, the further active ingredientis leptin.

[0231] In one embodiment, the further active ingredient isdexamphetamine, amphetamine, mazindole or phentermine.

[0232] In one embodiment, the compounds of the formula I areadministered in combination with medicaments having effects on thecoronary circulation and the vascular system, such as, for example, ACEinhibitors (e.g. ramipril), medicaments which act on theangiotensin-renine system, calcium antagonists, beta blockers etc.

[0233] In one embodiment, the compounds of the formula I areadministered in combination with medicaments having an antiinflammatoryeffect.

[0234] In one embodiment, the compounds of the formula I areadministered in combination with medicaments which are employed forcancer therapy and cancer prevention.

[0235] It will be appreciated that every suitable combination of thecompounds of the invention with one or more of the aforementionedcompounds and optionally one or more other pharmacologically activesubstances is regarded as falling within the protection conferred by thepresent invention.

[0236] The activity of the compounds was tested as follows:

[0237] Determination of EC50 values of PPAR agonists in the cellularPPARalpha assay

[0238] Principle

[0239] The potency of substances which bind to human PPARA and activatein an agonistic manner is analyzed using a stably transfected HEK cellline (HEK=human embryo kidney) which is referred to here as PPARalphareporter cell line. It contains two genetic elements, a luciferasereporter element (pδM-GAL4-Luc-Zeo) and a PPARalpha fusion protein(GR-GAL4-humanPPARα-LBD) which mediates expression of the luciferasereporter element depending on a PPARalpha ligand. The stably andconstitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD bindsin the cell nucleus of the PPARalpha reporter cell line via the GAL4protein portion to the GAL4 DNA binding motifs 5′-upstream of theluciferase reporter element which is integrated in the genome of thecell line. There is only little expression of the luciferase reportergene without addition of a PPARalpha ligand if fatty acid-depleted fetalcalf serum (cs-FCS) is used in the assay. PPARα ligands bind andactivate the PPARA fusion protein and thereby bring about expression ofthe luciferase reporter gene. The luciferase which is formed can bedetected by means of chemiluminescence via an appropriate substrate.

[0240] Construction of the cell line

[0241] The PPARalpha reporter cell line was prepared in 2 stages.Firstly, the luciferase reporter element was constructed and stablytransfected into HEK cells. For this purpose, five binding sites of theyeast transcription factor GAL4 (each 5′-CGGAGTACTGTCCTCCGAG-3′) (SEQ IDNo. 1) were cloned in 5′-upstream of a 68 bp-long minimal MMTV promoter(Genbank Accession # V01 175). The minimal MMTV promoter sectioncontains a CCAAT box and a TATA element in order to enable efficienttranscription by RNA polymerase 11. The cloning and sequencing of theGAL4-MMTV construct took place in analogy to the description of SambrookJ. et. al. (Molecular cloning, Cold Spring Harbor Laboratory Press,1989). Then the complete Photinus pyralis gene (Genbank Accession #M15077) was cloned in 3′-downstream of the GAL4-MMTV element. Aftersequencing, the luceriferase reporter element consisting of five GAL4binding sites, MMTV promoter and luciferase gene was recloned into aplasmid which confers zeocin resistance in order to obtain the plasmidpδM-GAL4-Luc-Zeo. This vector was transfected into HEK cells inaccordance with the statements in Ausubel, F. M. et al. (Currentprotocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc.,1995). Then zeocin-containing medium (0.5 mg/ml) was used to select asuitable stable cell clone which showed very low basal expression of theluceriferase gene.

[0242] In a second step, the PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD was introduced into the stable cell clonedescribed. For this purpose, initially the cDNA coding for theN-terminal 76 amino acids of the glucocorticoid receptor (GenbankAccession # P04150) was linked to the cDNA section coding for aminoacids 1-147 of the yeast transcription factor GAL4 (Genbank Accession #P04386). The cDNA of the ligand-binding domain of the human PPARalphareceptor (amino acids S167-Y468; Genbank Accession # S74349) was clonedin at the 3′-end of this GR-GAL4 construct. The fusion constructprepared in this way (GR-GAL4-humanPPARalpha-LBD) was recloned into theplasmid pcDNA3 (from Invitrogen) in order to enable constitutiveexpression therein by the cytomegalovirus promoter. This plasmid waslinearized with a restriction endonuclease and stably transfected intothe previously described cell clone containing the luciferase reporterelement. The finished PPARalpha reporter cell line which contains aluciferase reporter element and constitutively expresses the PPARalphafusion protein (GR-GAL4-human PPARalpha-LBD) was isolated by selectionwith zeocin (0.5 mg/ml) and G418 (0.5 mg/ml).

[0243] Assay procedure

[0244] The activity of PPARalpha agonists is determined in a 3-day assaywhich is described below:

[0245] Day 1

[0246] The PPARα-reporter cell line is cultivated to 80% confluence inDMEM (#41965-039, Invitrogen) which is mixed with the followingadditions: 10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5mg/ml zeocin (#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027,Invitrogen), 1% penicillin-streptomycin solution (#15140-122,Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). Thecultivation takes place in standard cell culture bottles (# 353112,Becton Dickinson) in a cell culture incubator at 37° C. in the presenceof 5% CO₂. The 80%-confluent cells are washed once with 15 ml of PBS(#14190-094, Invitrogen), treated with 3 ml of trypsin solution(#25300-054, Invitrogen) at 37° C. for 2 min, taken up in 5 ml of theDMEM described and counted in a cell counter. After dilution to 500.000cells/ml, 35,000 cells are seeded in each well of a 96 well microtiterplate with a clear plastic base (#3610, Corning Costar). The plates areincubated in the cell culture incubator at 37° C. and 5% CO₂ for 24 h.

[0247] Day 2

[0248] PPARalpha agonists to be tested are dissolved in DMSO in aconcentration of 10 mM. This stock solution is diluted in DMEM(#41965-039, Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03,Hyclone), 2 mM L-glutamine (#25030-024, Invitrogen) and the previouslydescribed antibiotics (zeocin, G418, penicillin and streptomycin).

[0249] Test substances are tested in 11 different concentrations in therange from 10 μM to 100 pM. More potent compounds are tested inconcentration ranges from 1 μM to 10 pM or between 100 nM and 1 pM.

[0250] The medium of the PPARalpha reporter cell line seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. The DMSO concentration in the assay is less than 0.1%v/v in order to avoid cytotoxic effects of the solvent.

[0251] Each plate was charged with a standard PPARalpha agonist, whichwas likewise diluted in 11 different concentrations, in order todemonstrate the functioning of the assay in each individual plate. Theassay plates are incubated in an incubator at 37° C. and 5% CO₂ for 24h.

[0252] Day 3

[0253] The PPARα reporter cells treated with the test substances areremoved from the incubator, and the medium is aspirated off. The cellsare lyzed by pipetting 50 μl of Bright Glo reagent (from Promega) intoeach well of a 96 well microtiter plate. After incubation at roomtemperature in the dark for 10 minutes, the microtiter plates aremeasured in the luminometer (Trilux from Wallac). The measuring time foreach well of a microtiter plate is 1 sec.

[0254] Evaluation

[0255] The raw data from the luminometer are transferred into aMicrosoft Excel file.

[0256] Dose-effect plots and EC50 values of PPAR agonists are calculatedusing the XL.Fit program as specified by the manufacturer (IDBS).

[0257] The PPARalpha EC50 values for the compounds of Examples 1 to 91in this assay are in the range from 0.6 nM to >10 μM.

[0258] The results for the activity of some compounds of the inventionof the formula I are indicated in Table I below: TABLE 1 Example No.EC50 PPARalpha [nM] 1 41 5 69 8 24 18 1.5 22 43 25 6.2 35 84 36 14 470.8 52 22 60 26 81 0.6 91 78

[0259] It is evident from Table I that the compounds of the invention ofthe formula I activate the PPARalpha receptor and thus bring about forexample in analogy to fibrates in clinical use a lowering oftriglycerides in the body (see, for example, J.-Ch. Fruchard et al.:PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research,Vol. 44, No. 5, 345-52, 2001; S. Kersten et al.: Roles of PPARs inhealth and disease, NATURE, VOL 405, 25 MAY 2000, 421-4; I. Pineda etal.: Peroxisome proliferator-activated receptors: from transcriptionalcontrol to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

[0260] Determination of EC50 values of PPAR agonists in the cellularPPARgamma assay

[0261] Principle

[0262] A transient transfection system is employed to determine thecellular PPARgamma activity of PPAR agonists. It is based on the use ofa luciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgammaexpression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids aretransiently transfected into human embryonic kidney cells (HEK cells).There is then expression in these cells of the fusion proteinGAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of thereporter plasmid. In the presence of a PPARgamma-active ligand, theactivated fusion protein GAL4-humanPPARgammaLBD induces expression ofthe luciferase reporter gene, which can be detected in the form of achemiluminescence signal after addition of a luciferase substrate. As adifference from the stably transfected PPARalpha reporter cell line, inthe cellular PPARγ assay the two components (luciferase reporter plasmidand PPARgamma expression plasmid) are transiently transfected into HEKcells because stable and permanent expression of the PPARgamma fusionprotein is cytotoxic.

[0263] Construction of the plasmids

[0264] The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based onthe vector pGL3basic from Promega. The reporter plasmid is prepared bycloning five binding sites of the yeast transcription factor GAL4 (eachbinding site with the sequence 5′-CTCGGAGGACAGTACTCCG-3′) (SEQ ID No.2), together with a 160 bp-long thymidine kinase promoter section(Genbank Accession # AF027128) 5′-upstream into pGL3basic. 3′-downstreamof the thymidine kinase promoter is the complete luciferase gene fromPhotinus pyralis (Genbank Accession # M15077) which is already aconstituent of the plasmid pGL3basic used. The cloning and sequencing ofthe reporter plasmid pGL3basic-5xGAL4-TK took place in analogy to thedescription in Sambrook J. et. al. (Molecular cloning, Cold SpringHarbor Laboratory Press, 1989).

[0265] The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARγLBD wasprepared by first cloning the cDNA coding for amino acids 1-147 of theyeast transcription factor GAL4 (Genbank Accession # P04386) into theplasmid pcDNA3 (from Invitrogen) 3′-downstream of the cytomegaloviruspromoter. Subsequently, the cDNA of the ligand-binding domain (LBD) ofthe human PPARγ receptor (amino acids 1152-Y475; Accession # g1480099)3′-downstream of the GAL4 DNA binding domain. Cloning and sequencing ofthe PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD againtook place in analogy to the description in Sambrook J. et. al.(Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Besidesthe luciferase reporter plasmid pGL3basic-5×GAL4-TK and the PPARγexpression plasmid pcDNA3-GAL4-humanPPARgammaLBD, also used for thecellular PPARgamma assay are the reference plasmid PRL-CMV (fromPromega) and the plasmid pBluescript SK(+) from Stratagene. All fourplasmids were prepared using a plasmid preparation kit from Qiagen,which ensured a plasmid quality with a minimal endotoxin content, beforetransfection into HEK cells.

[0266] Assay procedure

[0267] The activity of PPARgamma agonists is determined in a 4-day assaywhich is described below. Before the transfection, HEK cells arecultivated in DMEM (#41965-039, Invitrogen) which is mixed with thefollowing additions: 10% FCS (#16000-044, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen).

[0268] Day 1

[0269] Firstly, solution A, a transfection mixture which contains allfour plasmids previously described in addition to DMEM, is prepared. Thefollowing amounts are used to make up 3 ml of solution A for each 96well microtiter plate for an assay: 2622 μl of antibiotic- andserum-free DMEM (# 41965-039, Invitrogen), 100 μl of reference plasmidPRL-CMV (1 ng/μl), 100 μl of luciferase reporter plasmidpGL3basic-5xGAL4-TK (10 ng/pl), 100 μl of PPARγ expression plasmidpcDNA3-GAL4-humanPPARγLBD (100 ng/μl) and 78 μl of plasmid pBluescriptSK(+) (500 ng/pl). Then 2 ml of solution B are prepared by mixing 1.9 mlof DMEM (# 41965-039, Invitrogen) with 100 μl of PolyFect transfectionreagent (from Qiagen) for each 96 well microtiter plate. Subsequently, 3ml of solution A are mixed with 2 ml of solution B to give 5 ml ofsolution C, which is thoroughly mixed by multiple pipetting andincubated at room temperature for 10 min.

[0270] 80%-confluent HEK cells from a cell culture bottle with acapacity of 175 cm² are washed once with 15 ml of PBS (#14190-094,Invitrogen) and treated with 3 ml of trypsin solution (#25300-054,Invitrogen) at 37° C for 2 min. The cells are then taken up in 15 ml ofDMEM (#41965-039, Invitrogen) which is mixed with 10% FCS (# 16000-044,Invitrogen), 1% penicillin-streptomycin solution (#15140-122,Invitrogen) and 2 mM L-glutamine (#25030-024, Invitrogen). After thecell suspension has been counted in a cell counter, the suspension isdiluted to 250,000 cells/ml. 15 ml of this cell suspension are mixedwith 5 ml of solution C for one microtiter plate. 200 μl of thesuspension are seeded in each well of a 96 well microtiter plate with aclear plastic base (#3610, Corning Costar). The plates are incubated ina cell culture incubator at 37° C. and 5% CO₂ for 24 h.

[0271] Day 2

[0272] PPAR agonists to be tested are dissolved in DMSO in aconcentration of 10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen) which is mixed with 2% Ultroser (#12039-012,Biosepra), 1% penicillin-streptomycin solution (#15140-122, Invitrogen)and 2 mM L-glutamine (#25030-024, Invitrogen). Test substances aretested in a total of 11 different concentrations in the range from 10 μMto 100 pM. More potent compounds are tested in concentration ranges from1 μM to 10 pM.

[0273] The medium of the HEK cells transfected and seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. Each plate is charged with a standard PPARγ agonist,which is likewise diluted in 11 different concentrations, in order todemonstrate the functioning of the assay in each individual plate. Theassay plates are incubated in an incubator at 37° C. and 5% CO₂.

[0274] Day 4

[0275] After removal of the medium by aspiration, 50 μl of Dual-G loreagent (Dual-Glo™ Luciferase Assay System; Promega) are added to eachwell in accordance with the manufacturer's instructions in order to lyzethe cells and provide the substrate for the firefly luciferase (Photinuspyralis) formed in the cells. After incubation at room temperature inthe dark for 10 minutes, the firefly luciferase-mediatedchemiluminescence is measured in a measuring instrument (measuringtime/well 1 sec; Trilux from Wallac). Then 50 μl of the Dual-Glo™ Stop &Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added toeach well in order to stop the activity of the firefly luciferase andprovide the substrate for the Renilla luciferase expressed by thereference plasmid pRL-CMV. After incubation at room temperature in thedark for a further 10 minutes, a chemiluminescence mediated by theRenilla luciferase is again measured for 1 sec/well in the measuringinstrument.

[0276] Evaluation

[0277] The crude data from the luminometer are transferred into aMicrosoft Excel file. The firefly/Renilla luciferase activity ratio isdetermined for each measurement derived from one well of the microtiterplate. The dose-effect plots and EC50 values of PPAR agonists arecalculated from the ratios by the XL.Fit program as specified by themanufacturer (IDBS).

[0278] PPARgamma EC50 values in the range from 6nM to >10 μM weremeasured for the PPAR agonists described in this application.

[0279] The citation of any reference herein should not be construed asan admission that such reference is available as “Prior Art” to theinstant application.

[0280] The present invention is not to be limited in scope by thespecific embodiments describe herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

[0281] Various publications are cited herein, the disclosures of whichare incorporated by reference in their entireties.

[0282] The examples below serve to illustrate the invention, but withoutlimiting it. TABLE II

hereinbelow: Ring A = cis-cyclohexane-1,3-diyl, W = CH if o = 1, R4 = R5= R5 = R8 = H. Ex. R1 R2 R3 X Y1 Y2 n R6 R7 R9 R10 1 4-F H Me CH2O O CH21 H Et — — 2 4-F H Me CH2O O CH2 1 H n-Pr — — 3 4-F H Me CH2O O CH2 1 HH — — 4 4-F H Me CH2O O CH2 1 H Me — — 5 3-Me H Me CH2O O CH2 0cyclopropyl — — 6 3-Me H Me CH2O O CH2 0 H CH2NR9R10 Me Bn 7 3-Me H MeCH2O O CH2 0 H CH2NR9R10 Me PhCH2CH2 8 3-Me H Me CH2O O CH2 0 H MeOCH2 —— 9 3-Me H Me CH2O O CH2 0 H

— — 10 3-Me H Me CH2O O CH2 0 H n-PrO — — 11 3-Me H Me CH2O O CH2 0 H4-CF₃—(C6H4)—CH2O — — 12 3-Me H Me CH2O O CH2 0 H MeO — — 13 3-Me H MeCH2O O CH2 0 H 4-CF₃—(C6H4)—CH2O — — 14 3-Me H Me CH2O O CH2 0 H3-CF₃—(C6H4)—CH2O — — 15 3-Me H Me CH2O O CH2 0 H 3-MeO—(C6H4)—CH2O — —16 3-Me H Me CH2O O CH2 0 H 2-Me-4-Me-(C6H4)—CH2O — — 17 3-Me H Me CH2OO CH2 0 H 4-Me-(C6H4)—CH2O — — 18 3-Me H Me CH2O O CH2 0 H4-^(t)Bu--(C6H4)—CH2O — — 19 3-Me H Me CH2O O CH2 0 H 2-CF₃—(C6H4)—CH2O— — 20 3-Me H Me CH2O O CH2 0 H

— — 21 3-Me H Me CH2O O CH2 0 H

— — 22 3-Me H Me CH2O O CH2 0 H

— — 23 3-Me H Me CH2O O CH2 0 H

— — 24 3-Me H Me CH2O O CH2 0 H

— — 25 3-Me H Me CH2O O CH2 0 H

— — 26 3-Me H Me CH2O O CH2 0 H

— — 27 3-Me H Me CH2O O CH2 0 H BnO — — 28 H H Me CH2O O CH2 0 H MeO — —29 3-CF3 H Me CH2O O CH2 0 H MeO — — 30 3-OCF3 H Me CH2O O CH2 0 H MeO —— 31 4-CF3 H Me CH2O O CH2 0 H MeO — — 32 4-Me H Me CH2O O CH2 0 H MeO —— 33 2-Me 6-Me Me CH2O O CH2 0 H MeO — — 34 2-CF3 H Me CH2O O CH2 0 HMeO — — 35 2-Naphthyl Me CH2O O CH2 0 H MeO — — 36 2-Me 4-Me Me CH2O OCH2 0 H MeO — — 37 4-Ph H Me CH2O O CH2 0 H MeO — — 38 3-OMe H Et CH2O OCH2 0 H MeO — — 39 4-Me H Et CH2O O CH2 0 H MeO — — 40 2-CF3 H Et CH2O OCH2 0 H MeO — — 41 2-Me 6-Me Et CH2O O CH2 0 H MeO — — 42 H H Me CH2O OCH2 0 H n-PrO — — 43 3-Me H Me CH2O O CH2 0 H n-PrO — — 44 3-OCF3 H MeCH2O O CH2 0 H n-PrO — — 45 3-OMe H Me CH2O O CH2 0 H n-PrO — — 46 4-CF3H Me CH2O O CH2 0 H n-PrO — — 47 4-Me H Me CH2O O CH2 0 H n-PrO — — 484-CF3 H Me CH2O O CH2 0 H n-PrO — — 49 4-i-Pr H Me CH2O O CH2 0 H n-PrO— — 50 2-CF3 H Me CH2O O CH2 0 H n-PrO — — 51 2-Naphthyl Me CH2O O CH2 0H n-PrO — — 52 3-CF3 H Me CH2O O CH2 0 H n-PrO — — 53 3-OMe H Et CH2O OCH2 0 H n-PrO — — 54 4-Me H Et CH2O O CH2 0 H n-PrO — — 55 2-CF3 H EtCH2O O CH2 0 H n-PrO — — 56 2-Me 6-Me Et CH2O O CH2 0 H n-PrO — — 573-CF3 H Me CH2O O CH2 0 H EtO — — 58 3-OCF3 H Me CH2O O CH2 0 H EtO — —59 4-CF3 H Me CH2O O CH2 0 H EtO — — 60 4-OCF3 H Me CH2O O CH2 0 H EtO —— 61 4-i-Pr H Me CH2O O CH2 0 H EtO — — 62 2-CF3 H Me CH2O O CH2 0 H EtO— — 63 2-Me 4-Me Me CH2O O CH2 0 H EtO — — 64 4-Ph H Me CH2O O CH2 0 HEtO — — 65 4-Me H Et CH2O O CH2 0 H EtO — — 66 4-i-Pr H Et CH2O O CH2 0H EtO — — 67 2-CF3 H Et CH2O O CH2 0 H EtO — — 68 2-Me 6-Me Et CH2O OCH2 0 H EtO — — 69 4-i-Pr H Et CH2O O CH2 0 H n-PrO — — 70 H H Me CH2O OCH2 0 H EtO — — 71 3-Me H Me CH2O O CH2 0 H EtO — — 72 3-OMe H Me CH2O OCH2 0 H EtO — — 73 4-Me H Me CH2O O CH2 0 H EtO — — 74 2-Naphthyl MeCH2O O CH2 0 H EtO — — 75 3-OMe H Et CH2O O CH2 0 H EtO — — 76 3-Me H MeCH2O O CH2 0 H 4-CF3—(C6H4)—CH2O — — 77 3-CF3 H Me CH2O O CH2 0 H4-CF3—(C6H4)—CH2O — — 78 3-OCF3 H Me CH2O O CH2 0 H 4-CF3—(C6H4)—CH2O —— 79 4-i-Pr H Me CH2O O CH2 0 H 4-CF3—(C6H4)—CH2O — — 80 2-Naphthyl MeCH2O O CH2 0 H 4-CF3—(C6H4)—CH2O — — 81 4-Me H Me CH2O O CH2 0 H4-CF3—(C6H4)—CH2O — — 82 4-OCF3 H Me CH2O O CH2 0 H 4-CF3—(C6H4)—CH2O —— 83 4-CF3 H Me CH2O O CH2 0 H 4-CF3—(C6H4)—CH2O — — 84 3-OMe H Me CH2OO CH2 0 H 4-CF3—(C6H4)—CH2O — — 85 3-CF3 H Me CH2O O CH2 0 H i-BuO — —86 3-OMe H Me CH2O O CH2 0 H i-BuO — — 87 4-Me H Me CH2O O CH2 0 H i-BuO— — 88 4-i-Pr H Me CH2O O CH2 0 H i-BuO — — 89 3-Me H Me CH2OCH2 O CH2 0H 4-CF3—(C6H4)—CH2O — — 90 3-Me H Me CH2OCH2 O CH2 0 H 4-CF3—(C6H4)—CH2O— — 91 3-Me H Me CH2O O CH2 1 H m-CF3—(C6H4)—CH2 — —

[0283] The compounds of the formula I according to the invention can beobtained according to the reaction schemes below:

[0284] Process A:

[0285] This process is used for synthesizing the building block A-A inwhich R1, R2, W and R3 are as defined above.

[0286] Using sodium nitrite and hydrochloric acid, ester A-1, in whichR3 is as defined above is converted into oxime A-2 which is reduced toamine A-3 by hydrogenation with hydrogen over palladium/carbon.

[0287] Using acid chlorides of the formula A4 in which R1, W and R2 areas defined above and base (for example triethylamine), compound A-3 isconverted into compound A-5.

[0288] By heating in phosphoryl chloride, compound A-5 is converted intocompound A-6. Using lithium aluminum hydride in diethyl ether, ester A-6is reduced to alcohol A-7. This is converted into iodide A-8 usingiodine, imidazole (ImH) and triphenylphosphine.

[0289] Process B:

[0290] This process is used for synthesizing the building block A-8 inwhich R1, R2, W and R3 are as defined above.

[0291] In ethanol and using hydrogen chloride, compound B-1 is reactedwith aldehyde B-2 in which R1, R2, W and R3 are as defined above, togive compound B-3. Compound B-3 is heated to the boil in phosphorylchloride, giving compound B-4. This is heated to the boil with sodiumiodide in acetone. This gives compound A-8.

[0292] Process C:

[0293] Compound C-1 is boiled with dibutyltin oxide in toluene underreflux on a water separator. Following addition of dimethylformamide,cesium fluoride and compound A-8 (see process A), the suspension isstirred at room temperature. This gives compound C-2. This is convertedwith Chirazyme L-2 in vinyl acetate into the enantiomerically enrichedacetate C-3. Acetate C-3 is converted with sodium hydroxide in methanolinto alcohol C4.

[0294] Compound C-4 is reacted with sodium hydride and allyl bromide indimethylformamide at room temperature, to give compound C-5.

[0295] Compound C-5 is reacted with osmium tetroxide and sodiumperiodate in diethyl ether, to give compound C-6. This is reacted in aHorner-Emmons-Wadsworth reaction with sodium hydride and compound C-7 togive compound C-8.

[0296] Compound C-8 is hydrolyzed to the free acid by stirring at roomtemperature with sodium hydroxide in methanol for a number of hours. Theresulting compound C-9 is hydrogenated with hydrogen overpalladium/carbon to compound C-10.

[0297] According to this process, it is possible to synthesize examples1 to 4.

[0298] Process D:

[0299] Compound C-2 is reacted with sodium hydride and ethyl2-bromomethylacrylate in dimethylformamide at 0C, to give compound D-1.

[0300] Compound D-1 is then reacted either with trimethylsulfoniumiodide and sodium hydride in dimethyl sulfoxide, to give compound D-2,or with a secondary amine NR10R11, where R10 and R11 are as definedabove, to give compound D-3, or with an aryl halide and a palladium(O)catalyst in a Heck reaction, to give compound D-4. Compound D-4 is thenhydrogenated with hydrogen over palladium on carbon, to give compoundD-5.

[0301] Compounds D-2, D-3 and D-5 are converted with sodium hydroxideinto compounds of the general formula D-6, where R6 and R7 are asdefined above. According to this process, it is possible to synthesizeexamples 5 to 9.

[0302] Process E:

[0303] Compound C-5 is dihydroxylated with osmium tetroxide,1,5-diazabicyclo[2.2.2]-octane (DABCO) and N-methylmorpholine N-oxide,to give compound E-1. The primary hydroxyl group is then protected astrialkylsilyl ether E-2 by stirring compound E-1 with atrialkylchlorosilane (for example tert-butyldimethylsilyl chloride) andimidazole as base in dimethylformamide at room temperature. Compound E-2is then reacted with a strong base (for example sodium hydride orpotassium tert-butoxide) and an alkyl halide to give compound E-3 inwhich R7 is as defined above. The silyl protective group is removedusing tetrabutylammonium fluoride in tetrahydrofuran, to give compoundE-4.

[0304] Compound E-4 is stirred with Dess-Martin periodinane (DMP) indichloromethane at room temperature for a number of hours, worked up andthen reacted with sodium chlorite and hydrogen peroxide in acetonitrile,to give compound E-5. Alternatively, E-5 can be synthesized by directoxidation of E-4 using a chromium(VI) compound (for example CrO3 insulfuric acid).

[0305] According to this process, it is possible to synthesize examples10 to 27.

[0306] Process F:

[0307] This process is used for an alternative preparation ofintermediates E-3 (see process E)

[0308] The racemic or enantiomerically pure compound F-1 in which PG hasthe meaning indicated in the scheme is dihydroxylated with osmiumtetroxide, 1,5-diazabicyclo-[2.2.2]octane (DABCO) and N-methylmorpholineN-oxide, to give compound F-2. The primary hydroxyl group is thenprotected as trialkylsilyl ether F-3 by stirring compound F-2 with atrialkylchlorosilane (for example tert-butyldimethylsilyl chloride) andimidazole as base in dimethylformamide at room temperature.

[0309] Compound F-3 is then reacted with a strong base (for examplesodium hydride or potassium tert-butoxide) and an alkyl halide, to givecompound F-4, where R7 is as defined above. The benzyl protective groupis removed hydrogenolytically using hydrogen over Pd (10% on carbon),the benzoyl protective group is removed using potassium carbonate inmethanol and the trityl group is removed using formic acid in methanol,to give compound F-5.

[0310] Using alkyl iodide A-8 in the presence of a strong base (forexample sodium hydride or potassium tert-butoxide) in an inert solvent(for example MTBE, chlorobenzene), compound E-5 is converted intocompound E-3 in which R1, R2, R3, R7 and W are as defined above.

[0311] The subsequent conversions of E-3 into E-5 are then carried outas described under process E.

[0312] According to this process, it is possible to synthesize examples28 to 90.

[0313] Process G:

[0314] Compound G-1 (3-aminobenzoic acid) is hydrogenated in acetic acidusing 5 hydrogen over platinum dioxide under elevated pressure, to givecompound G-2. Using thionyl chloride in an alcohol R8OH in which R8 isas defined above (except for R8=H), this compound is converted to anester, to give compound G-3. Compound G-3 is then reacted with benzylbromide and potassium carbonate, to give dibenzylamine G-4. Reduction ofG4 with LiAIH4 gives alcohol G-5.

[0315] Using an alkyl iodide A-8, compound G-5 is converted intocompound G-6 in which R1, R2, W and R3 are as defined above. Usinghydrogen over palladium, compound G-6 is hydrogenated to compound G-7 inwhich R1, R2, W and R3 are as defined above.

[0316] Compound G-7 is coupled with carboxylic acid derivatives G-8 inwhich R4, R5, R6 and R7 are as defined above. If dicarboxylic acidmonoesters G-8 are used, the coupling is followed by an ester hydrolysis(using, for example, LiOH in THF/methanol/water for R8=methyl or ethyl).This gives compound G-9 in which R1, R2, W, R3, R4, R5, R6 and R 7 areas defined above.

[0317] According to this process, it is possible to synthesize examples28 to 90.

[0318] The abbreviations used denote:

[0319] Ac acetyl

[0320] Bn benzyl

[0321]^(i)Bu isobutyl

[0322]^(t)Bu tert-butyl

[0323] BuLi n-butyllithium

[0324] Bz benzoyl

[0325] Cy cyclohexyl

[0326] TLC thin-layer chromatography

[0327] DCI direct chemical ionization (in MS)

[0328] DCM dichloromethane

[0329] DMAP 4-N,N-dimethylaminopyridine

[0330] DMF N,N-dimethylformamide

[0331] DMSO dimethyl sulfoxide

[0332] EE ethyl acetate

[0333] EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl

[0334] EI electron impact ionization (in MS)

[0335] eq equivalent

[0336] ESI electron spray ionization (in MS)

[0337] Et ethyl

[0338] sat. saturated

[0339] h hour

[0340] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

[0341] HOBt 1-hydroxy-1H-benzotriazole×H₂O

[0342] HPLC high pressure, high performance liquid chromatography

[0343] LC-MS liquid chromatography-coupled mass spectroscopy

[0344] Me methyl

[0345] MS mass spectroscopy

[0346] MsCl methanesulfonyl chloride

[0347] NMR nuclear magnetic resonance spectroscopy

[0348] Pd/C palladium on carbon

[0349]^(i)Pr isopropyl

[0350]^(n)Pr n-propyl

[0351] R_(f) retention time (in TLC)

[0352] RT room temperature

[0353] TBAF tetrabutylammonium fluoride

[0354] TBAI tetrabutylammonium iodide

[0355] TBDPSCl tert-butyldiphenylsilyl chloride

[0356] TBDMSCl tert-butyIdimethylsilyl chloride

[0357] THF tetrahydrofuran

[0358] Tr trityl

[0359] It is possible to prepare other compounds by the processesmentioned above.

[0360] Building block synthesis according to process A:

[0361] 42.4 g of ethyl 4-methyl-3-oxopentanoate are dissolved in 100 mlof glacial acetic acid, and 21 g of sodium nitrite, dissolved in 100 mlof water, are added at 5° C. Over a period of one hour, the mixture isallowed to warm to room temperature, 100 ml of water are added and themixture is stirred at room temperature for another hour. The mixture isextracted three times with in each case 150 ml of methyl tert-butylether, 200 ml of water are added to the combined organic phases and themixture is neutralized by addition of solid NaHCO3. The organic phase isremoved, washed with saturated NaCI solution and dried over MgSO4, andthe solvent is removed under reduced pressure. This gives 46 g of ethyl2-hydroxy-imino-4-methyl-3-oxopentanoate as an oil. C8H13NO4 (187.20),MS (ESI) =188 (M+H⁺).

[0362] Ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride

[0363] 10 g of HCl are introduced into 200 ml of ethanol. 46 g of ethyl2-hydroxyimino4-methyl-3-oxopentanoate are dissolved in this mixture, 5g of Pd (10% on carbon) are added and the mixture is stirred under anatmosphere of hydrogen (5 bar) for 8 hours. The reaction mixture isfiltered through Celite and the solvent is removed under reducedpressure. This gives 45 g of ethyl 2-amino-4-methyl-3-oxopentanoatehydrochloride as a white solid. C8H15NO3*HCl (209.5), MS(ESI)=188(M+H⁺).

[0364] Ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate

[0365] 10 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and7.4 g of 4-methylbenzoyl chloride are dissolved in 250 ml ofdichloromethane, and 13.3 ml of triethylamine are slowly added dropwiseat 0° C. The mixture is stirred at room temperature for one hour andthen washed with water, the organic phase is separated off and driedover MgSO4, and the solvent is then removed under reduced pressure. Thisgives 13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate asan oil. C16H21NO4 (291.35), MS(ESI)=292 (M+H⁺).

[0366] Ethyl 5-isopropyl-2-p-tolyloxazole4-carboxylate

[0367] 13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoatein 80 ml of phosphorus oxychloride are heated to the boil under refluxfor 2 h. The phosphorus oxychloride is removed under reduced pressureand the resulting residue is dissolved in 200 ml of dichloromethane,washed three times with saturated NaHCO₃ solution and dried over MgSO4,and the solvent is then removed under reduced pressure. This gives 11 gof ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate as a brownish solid.C16H19NO3 (273.33), MS(ESI)=292 (M+H⁺), Rf(n-heptane:ethylacetate)=2:1)=0.43.

[0368] (5-Isopropyl-2-p-tolyloxazol-4-yl)methanol

[0369] 11 g of ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate aredissolved in 100 ml of tetrahydrofuran, and 40 ml of a 1 molar solutionof lithium aluminum hydride in tetrahydrofuran are added at 0C. After 30min, 50 ml of 1 N HCl are added to the reaction mixture, and the mixtureis extracted five times with ethyl acetate. The combined organic phasesare dried over MgSO4, and the solvent is then removed under reducedpressure. The residue is purified on silica gel using the mobile phasen-heptane:ethyl acetate=6:1=>1:1. This gives 4.3 g of(5-isopropyl-2-p-tolyloxazol4-yl)methanol as a light-yellow solid.C14H17NO2 (231.30), MS(ESI)=232 (M+H⁺), Rf(n-heptane:ethylacetate)=1:1)=0.17

[0370] 4-lodomethyl-5-isopropyl-2-p-tolyloxazole

[0371] 500 mg of (5-isopropyl-2-p-tolyloxazol-4-yl)methanol, togetherwith 690 mg of triphenylphosphine and 600 mg of imidazole, are dissolvedin 20 ml of toluene. 715 mg of iodine are added, and the mixture isstirred at room temperature for 1 hour. 10 ml of saturated sodiumcarbonate solution and 500 mg of iodine are then added. After 10minutes, the organic phase is separated off, washed twice with saturatedNa2S2O3 solution and dried over MgSO4, and the solvents are then removedunder reduced pressure. The residue is purified on silica gel using themobile phase n-heptane:ethyl acetate=10:1. This gives 400 mg of4-iodomethyl-5-isopropyl-2-p-tolyloxazole as a white solid. C14H16INO(341.19), MS(ESI): 342 (M+H⁺), Rf(n-heptane:ethyl acetate=1:1)=0.75.

[0372] Analogously to the building block synthesis according to processA, ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and3-methoxybenzoyl chloride gave4-iodomethyl-2-(3-methoxyphenyl)-5-isopropyloxazole.

[0373] C14H161NO2 (357.19), MS(ESI): 358 (M+H⁺), Rf(n-heptane:ethylacetate=1:1)=0.60.

[0374] Analogously to the building block synthesis of4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole, ethyl4,4,4-trifluoro-3-oxobutyrate and 3-methoxybenzoyl chloride gave4-iodomethyl-2-(3-methoxyphenyl)-5-trifluoromethyloxazole.

[0375] C12H9F31NO2 (383.11), MS(ESI): 384 (M+H⁺).

[0376] Analogously to the building block synthesis of4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole, ethyl4,4,4-trifluoro-3-oxobutyrate and 3-trifluoromethylbenzoyl chloride gave4-iodomethyl-2-(3-trifluoromethylphenyl)-5-trifluoromethyloxazole.

[0377] C12H6F61NO (421.08), MS(ESI): 422 (M+H⁺).

[0378] Analogously to the building block synthesis of4-iodomethyl-5-isopropyl-2-p-tolyl-oxazole, ethyl4,4,4-trifluoro-3-oxobutyrate and 4-methylbenzoyl chloride gave4-iodomethyl-5-trifluoromethyl-2-p-tolyloxazole.

[0379] C12H9F31NO (367.11), MS(ESI): 368 (M+H⁺).

[0380] Building block synthesis according to process B:

[0381] 12.5 g of 1-phenyl-1,2-propanedione-2-oxime and 10 ml ofp-tolualdehyde are added to 50 ml of glacial acetic acid, and HCl gas isintroduced for 30 minutes, with ice-cooling. The product is precipitatedas the hydrochloride by addition of methyl tert-butyl ether and filteredoff with suction, and the precipitate is washed with methyl tert-butylether. The precipitate is suspended in water and the pH is made alkalineusing ammonia. The mixture is extracted three times with in each case200 ml of dichloromethane, the combined organic phases are dried overMgSO4 and the solvent is then removed under reduced pressure. This gives6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide as a white solid.C17H1 5NO2 (265.31), MS(ESI)=266 (M+H⁺).

[0382] 4-Chloromethyl-5-phenyl-2-p-tolyloxazole

[0383] 6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide are dissolvedin 50 ml of chloroform, 2.4 ml of phosphorus oxychloride are added andthe mixture is, under reflux, heated at the boil for 30 minutes. Thereaction mixture is cooled to 0° C., the pH is made slightly alkalineusing ammonia and the mixture is extracted three times with in each case100 ml of ethyl acetate. The combined organic phases are washed withwater and dried over MgSO4, and the solvent then removed under reducedpressure. This gives 5.4 g of 4-chloromethyl-5-phenyl-2-p-tolyloxazoleas a yellow solid. C17H14CINO (283.76), MS(ESI)=284 (M+H⁺),Rf(n-heptane:ethyl acetate)=7:1)=0.41.

[0384] 4-lodomethyl-5-phenyl-2-p-tolyloxazole

[0385] Together with 3 g of sodium iodide, 1.8 g of4-chloromethyl-5-phenyl-2-p-tolyloxazole are, in 150 ml of acetone,heated at the boil under reflux for 2 hours. After cooling of thereaction mixture, 300 ml of methyl tert-butyl ether are added, themixture is washed three times with saturated Na2S203 solution and driedover MgSO4, and the solvents are then removed under reduced pressure.This gives 2.7 g of 4-iodomethyl-5-phenyl-2-p-tolyloxazole as alight-yellow solid. C17H14INO (375.21), MS(ESI): 376 (M+H⁺).

[0386] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-phenyl-1,2-propanedione-2-oxime and m-anisaldehyde gave4-iodomethyl-2-(3-methoxyphenyl)-5-phenyloxazole.

[0387] C17H14INO2 (391.21), MS(ESI): 392 (M+H⁺).

[0388] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-ethyl-1,2-propanedione-2-oxime and m-anisaldehyde gave4-iodo-methyl-5-ethyl-2-(3-methoxyphenyl)oxazole.

[0389] C13H14INO2 (343.17), MS(ESI): 344 (M+H⁺).

[0390] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-ethyl-1,2-propanedione-2-oxime and p-tolualdehyde gave4-iodomethyl-5-ethyl-2-p-tolylazole.

[0391] C13H14INO (327.17), MS(ESI): 328 (M+H⁺).

[0392] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-ethyl-1,2-propanedione-2-oxime and 2,6-dimethylbenzaldehyde gave4-iodomethyl-5-ethyl-2-(2,6-dimethylphenyl)oxazole.

[0393] C14H16INO (341.19), MS(ESI): 342 (M+H⁺).

[0394] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-ethyl-1,2-propanedione-2-oxime and 2-trifluoromethylbenzaldehyde gave4-iodomethyl-5-ethyl-2-(2-trifluoromethylphenyl)oxazole.

[0395] C13H11F3INO (381,14), MS(ESI): 382 (M+H⁺).

[0396] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-cyclohexyl-1,2-propanedione-2-oxime and m-anisaldehyde gave4-iodomethyl-5-cyclohexyl-2-(3-methoxyphenyl )oxazole.

[0397] C17H20INO2 (397.26), MS(ESI): 398 (M+H⁺).

[0398] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole,1-cyclohexyl-1,2-propanedione-2-oxime and p-tolualdehyde gave4-iodomethyl-5-cyclohexyl-2-p-tolyloxazole.

[0399] C17H20INO (381.26), MS(ESI): 382 (M+H⁺).

[0400] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime andp-tolualdehyde gave 4-iodomethyl-5-methyl-2-p-tolyloxazole.

[0401] C12H12INO (313.14), MS(ESI): 314 (M+H⁺).

[0402] Analogously to the building block synthesis of4-chloromethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime andbenzaldehyde gave 4-chloromethyl-5-methyl-2-phenyloxazole.

[0403] C11H10INO (207.66), MS(ESI): 208 (M+H⁺).

[0404] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-biphenyl-oxazole, diacetylmonoxime andp-biphenylcarbaldehyde gave 4-iodomethyl-5-methyl-2-p-biphenyloxazole.

[0405] C12H12INO (375.21), MS(ESI): 376 (M+H⁺).

[0406] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and2-naphthalenecarbaldehyde gave 4-iodomethyl-5-methyl-2-naphthyloxazole.

[0407] C12H12INO (349.17), MS(ESI): 350 (M+H⁺).

[0408] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and2,4-dimethylbenzaldehyde gave4-iodomethyl-5-methyl-2-(2,4-dimethylphenyl)oxazole.

[0409] C13H14INO (327.17), MS(ESI): 328 (M+H⁺).

[0410] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and2,6-dimethylbenzaldehyde gave4-iodomethyl-5-methyl-2-(2,6-dimethylphenyl)oxazole.

[0411] C13H14INO (327,17), MS(ESI): 328 (M+H⁺).

[0412] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime andm-anisaldehyde gave 4-iodomethyl-2-(3-methoxy-phenyl)-5-methyloxazole.

[0413] C12H12INO2 (329.14), MS(ESI): 330 (M+H⁺).

[0414] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and3-trifluoromethylbenzaldehyde gave4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole.

[0415] C12H9F3INO (367.11), MS(ESI): 368 (M+H⁺).

[0416] Analogously to the-building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and4-fluorobenzaldehyde gave2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole.

[0417] C11H9FINO (317.1 0), MS(ESI):318 (M+H+).

[0418] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and4-methoxybenzaldehyde gave4-iodomethyl-2-(4-methoxyphenyl)-5-methyloxazole.

[0419] C12H12INO2 (329.14), MS(ESI):330 (M+H+).

[0420] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and4-trifluoromethylbenzaldehyde gave4-iodomethyl-5-methyl-2-(4-trifluoromethylphenyl)oxazole.

[0421] C12H9F3INO (367.11), MS(ESI):368 (M+H+).

[0422] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and2-trifluoromethylbenzaldehyde gave4-iodomethyl-5-methyl-2-(2-trifluoromethylphenyl)oxazole.

[0423] C12H9F3INO (367.11), MS(ESI):368 (M+H+).

[0424] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime andm-tolualdehyde gave 4-iodomethyl-5-methyl-2-m-tolyloxazole.

[0425] C12H12INO (313.14), MS(ESI):314 (M+H+).

[0426] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and3-trifluoromethoxybenzaldehyde gave4-iodo-methyl-5-methyl-2-(3-trifluoromethoxyphenyl)oxazole.

[0427] C12H9F3INO2 (383.11), MS(ESI):384 (M+H+).

[0428] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and5-methylfuran-2-carbaldehyde gave4-iodomethyl-5-methyl-2-(5-methylfuran-2-yl)oxazole.

[0429] C10H10INO2 (303.11), MS(ESI):304 (M+H+).

[0430] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime andthiophene-2-carbaldehyde gave4-iodomethyl-5-methyl-2-thiophen-2-yloxazole.

[0431] C9H8INOS (305.14), MS(ESI):306 (M+H+).

[0432] Analogously to the building block synthesis of4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and4-isopropylbenzaldehyde gave4-iodomethyl-2-(4-isopropylphenyl)-5-methyloxazole.

[0433] C14H16INO (341.19), MS(ESI):342 (M+H+).

EXAMPLE 1

[0434]2-Ethyl-4{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}butanoicacid

[0435] rac-3-(cis-5-Methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexanol

[0436] 21.7 g of 1,3-cyclohexanediol and 30.3 g of dibutyltin oxide aredissolved in 450 ml of toluene and, under reflux on a water separator,heated at the boil. During the reaction, the reaction volume is reducedto half the original volume. After 3 hours, the reaction mixture iscooled to room temperature and 300 ml of dimethylformamide, 29 g of2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole and 23.5 g of cesium.fluoride are added. The mixture is stirred at room temperature for 18hours. The reaction mixture is diluted by addition of ethyl acetate andwashed with saturated sodium chloride solution. The organic phase isdried over magnesium sulfate, the solvent is removed under reducedpressure and the residue is purified by flash chromatography on silicagel (n-heptane/ethyl acetate =10:1→1:4). This gives 58 g ofrac-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy ]cyclohexanol as ayellowish solid which is recrystallized from n-heptane/ethyl acetate.C17H20FNO3 (305.35), MS(ESI): 306 (M+H+).

[0437] 3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol

[0438] 25 g ofrac-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol aredissolved in 320 ml of vinyl acetate, and 1.3 g of Chirazyme L-2 Lyo(Boehringer Mannheim) are added. After about three hours of stirring atroom temperature (checked by LC-MS for 40-45% conversion), the enzyme isfiltered off and washed with ethyl acetate, and the solvent is removedunder reduced pressure. The residue is purified by flash chromatographyon silica gel (n-heptane/ethyl acetate =3:1). This gives 8 g of theacetate as a colorless oil. C19H22FNO4 (347.39), MS (ESI): 348 (M+H⁺).The acetate is taken up in 170 ml of methanol and, after addition of 27ml of 2N NaOH, stirred at room temperature for one hour. Most of thesolvent is removed under reduced pressure. After addition of in eachcase 150 ml of water and ethyl acetate, the organic phase is washed withsodium chloride solution. The organic phase is dried over magnesiumsulfate and the solvent is removed under reduced pressure. This gives6.7 g of3-(1R,3S)-cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanolas a yellowish solid. C17H20FNO3 (305.35), MS (ESI): 306 (M+H+).

[0439]4-(3-Allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole

[0440] 2 g of the3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy)cyclohexanol aredissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride isadded. After 30 minutes, 2.4 g of allyl bromide are added dropwise. Themixture is stirred at room temperature for 5 hours. 15 ml of 1 N HCl arethen added to the reaction mixture, and the mixture is washed threetimes with 15 ml of ethyl acetate. The organic phase is dried overmagnesium sulfate and the solvent is then removed under reducedpressure. The residue is purified by RP-HPLC. This gives 2.4 g of4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole asa yellowish oil. C20H24FNO3 (345.42) MS(ESI): 346 (M+H+)

[0441][3-[2-(4-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde

[0442] 2.0 g of4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole aredissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate,dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmiumtetroxide solution (2.5% by weight in tert-butanol) is added, and themixture is stirred vigorously at room temperature. After 8 h, 100 ml ofmethyl tert-butyl ether are added and the mixture is washed with asaturated sodium thiosulfate solution. The organic phase is dried overmagnesium sulfate and the solvent is removed under reduced pressure. Theresidue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5).This gives 1.4 g of[3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]-acetaldehyde as a yellow-brown oil. C20H25NO4 (343.42), MS(ESI): 344(M+H+), R_(f)(n-heptane:ethyl acetate=1:1)=0.25.

[0443] Ethyl2-ethyl4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}but-2-enoate

[0444] 0.58 g of ethyl 2-(diethoxyphosphoryl)butanoate is dissolved intetrahydrofuran (20 ml), and 0.06 g of sodium hydride is added at 0° C.The suspension is stirred at 0° C. for 30 min and at room temperaturefor 30 min and then cooled to −70° C. After addition of 0.4 g of2-((1R,3S)-[3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]acetaldehyde(dissolved in 5 ml of tetrahydrofuran), the mixture is stirred at −70°C. for 60 min and then at room temperature for 12 h. 10 ml of water areadded, the mixture is extracted with ethyl acetate (3×10 ml) and thecombined organic phases are washed with saturated sodium chloridesolution (10 ml). The solvent is removed under reduced pressure and theresidue is purified by HPLC. This gives 0.32 g of ethyl2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoateC25H32FNO5 (445.54) MS(ESI): 446 (M+H+)

[0445]2-Ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}but-2-enoicacid

[0446] 0.5 g of ethyl2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoate is dissolved in 5 ml of methanol, and 2.5 mlof a 1N aqueous sodium hydroxide solution are added. After 12 h ofstirring at room temperature, the mixture is acidified with 3 ml of 1 Nhydrochloric acid and the resulting precipitate is taken up in ethylacetate. The solvent is removed under reduced pressure and the residueof the ester hydrolysis,2-ethyl4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoicacid, is obtained as 0.45 g of a white solid. C23H28FNO₅ (417.48)MS(ESI): 418 (M+H⁺)

[0447]2-Ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}butanoicacid

[0448] 0.3 g of the 2-ethyl-4-{(1R,3S)-3-[2-(4fluorophenyl)-5-methyloxazol-4-ylmethoxy ]-cyclohexyloxy}but-2-enoicacid is dissolved in a solvent mixture of 2 ml of ethyl acetate and 1 mlof methanol, and 0.05 g of palladium (10% on carbon) is added. Themixture is then hydrogenated at a hydrogen pressure of 1 bar for 3 h.After removal of the palladium by filtration, the solvent mixture isremoved under reduced pressure and the residue is recrystallized fromacetonitrile. This gives 0.25 g of2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}butanoic acid as a white solid. C₂₃H₃₀FNO₅ (419.49),MS(ESI): 420 (M+H⁺)

EXAMPLE 2

[0449] Analogously to Example 1,2-((1R,3S)-[3-(2-(4-fluorophenyl)-5-methyloxazol-4-yl-methoxy)cyclohexyloxy]acetaldehydeand ethyl 2-(d iethoxyphosphoryl)pentanoate give2-propyl-4-[3-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy)cyclohexyloxy]-butanoicacid.

[0450] C₂₄H₃₂FNO₅ (433.52) MS(ESI): 434 (M+H⁺)

EXAMPLE 3

[0451] Analogously to Example 1,2-(1R,3S)-[3-(2-(4-fluorophenyl)-5-methyloxazol-4-yl-methoxy)cyclohexyloxy]acetaldehydeand ethyl 2-(diethoxyphosphoryl)acetate give4-{3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}butanoicacid

[0452] C₂₁H₂₆FNO₅ (391.44) MS(ESI): 392 (M+H⁺)

EXAMPLE 4

[0453] Analogously to Example 1,2-(1R,3S)-[3-(2-(4-fluorophenyl)-5-methyloxazol-4-yl-methoxy)cyclohexyloxy]acetaldehydeand ethyl 2-(diethoxyphosphoryl)propionate give4-{3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}-2-methyl-butanoicacid

[0454] C22H28FNO5 (405.47) MS(ESI): 406 (M +H+)

EXAMPLE 5

[0455] Ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]-acrylate

[0456] At room temperature, 200 mg of a 60% strength sodium hydridesuspension are added to a solution of 754 mg of3-(1R,3S)-cis-5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexanol in 10ml of dimethylformamide/ 5 ml of tetrahydrofuran, and the mixture isstirred at room temperature for 20 min. At 0° C., 1 g of ethyl2-bromo-methylacrylate is then added, and the mixture is stirred at thistemperature for 2 h.

[0457] 100 ml of ethyl acetate and 150 ml of sat. NaCl solution areadded. The organic phase is dried over sodium sulfate, the solvent isremoved under reduced pressure and the residue is purified by flashchromatography on silica gel (n-heptane/ethyl acetate=2:1). This gives1.18 g of ethyl((1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]acrylateas a colorless oil. C₂₄H₃₁ NO₅ (413.52), MS (ESI): 414 (M+H⁺).

[0458] Ethyl(1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]-cyclopropanecarboxylate

[0459] At room temperature, 12 mg of a 60 percent strength sodiumhydride suspension are added to a suspension of 55 mg oftrimethylsulfonium iodide in 2 ml of DMSO, and the mixture is stirred atroom temperature for 20 min. At 10° C, 100 mg of ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]acrylate,dissolved in 2 ml of DMSO, are then added, and the mixture is stirred atroom temperature for 90 min. The mixture is poured into ice-water andextracted with methyl tert-butyl ether. The organic phase is dried oversodium sulfate, the solvent is removed under reduced pressure and theresidue is purified by flash chromatography on silica gel(n-heptane/ethyl acetate=2:1). This gives ethyl(1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclo-propanecarboxylate as a colorless oil. C₂₅H₃₃NO₅ (427.55), MS(ESI): 428 (M+H⁺).

[0460](1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclo-propanecarboxylicacid

[0461] 56 mg of ethyl(1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)-cyclohexyloxymethyl]cyclopropanecarboxylateare dissolved in 3 ml of methanol, 0.5 ml of 5N NaOH is added and themixture is stirred at room temperature for 18 h. The solvent is removedunder reduced pressure and the residue is acidified with trifluoroaceticacid and purified by RP-HPLC. This gives(1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclopropanecarboxylicacid as a colorless oil. C₂₃H₂₉NO₅ (399.49), MS (ESI): 400 (M+H⁺).

EXAMPLE 6

[0462] Ethyl2R/S-(1R′,3S′)-2-[(methylphenethylamino)methyl]-3-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyloxy]propionate

[0463] 50 mg of ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclo-hexyloxymethyl]acrylateare dissolved in 5 ml of ethanol, 95 mg of N-methylhomo-benzylamine areadded and the mixture is stirred at room temperature for 18 h. Thesolvent is removed under reduced pressure and the residue is purified byflash chromatography on silica gel (n-heptane/ethyl acetate=1:1+3%NEt₃). This gives ethyl2R/S-(1R′,3S′)-2-[(methylphenethylamino)methyl]-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propionateas a colorless oil. C₃₃H₄₄N₂O₅ (548.73), MS (ESI): 549 (M+H⁺).

[0464] ((1R′,3S′)-2R/S-[(Methylphenethylamino)methyl]-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propionicacid

[0465] 65 mg of ethyl2R/S-((1R′,3S′)-2-[(methylphenethylamino)methyl]-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propionateare dissolved in 3 ml of tetrahydrofuran/methanol 3:1, 0.6 ml of 1N LiOHis added and the mixture is stirred at room temperature for 6 h. Thesolvent is removed under reduced pressure and the residue is acidifiedwith trifluoroacetic acid and purified by RP-HPLC. This gives2R/S-((1R′,3S′)[(methylphenethylamino)methyl]-3-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyloxy]propionicacid as a colorless oil. C₃₁ H₄₀N₂O₅ (520.67), MS (ESI): 521 (M+H⁺).

EXAMPLE 7

[0466]

[0467](1R′,3S′)-2R/S-[(Benzylmethylamino)methyl]-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]propionicacid

[0468] Ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy-methyl]acrylate and N-methylbenzylamine give, analogously to Example 100,(1R′,3S′)-2R/S-[(benzylmethylamino)methyl]-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]propionicacid of molecular weight 506.65 (C₃₀H₃₈N₂O₅), MS(ESI): 507.20 (M+H⁺).

EXAMPLE 8

[0469](1R′,3S′)-2R/S-Methoxymethyl-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclo-hexyloxy]propionicacid

[0470] 56 mg of ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy-methyl]acrylate are dissolved in 3 ml of methanol, 49 mg of sodium cyanide and0.25 ml of 2N NaOH are added and the mixture is stirred at roomtemperature for 18 h. The solvent is removed under reduced pressure andthe residue is acidified with trifluoroacetic acid and purified byRP-HPLC. This gives(1R′,3S′)-2R/S-methoxymethyl-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-propionic acid as a colorless oil. C₂₃H₃₁NO₆ (417.51), MS (ESI):418.15 (M+H⁺).

EXAMPLE 9

[0471] EthylZ-(1R′,3S′)-3-(4-fluoro-3-methylphenyl)-2-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxymethyl]acrylate

[0472] 220 mg of tetrabutylammonium chloride and 332 mg of potassiumcarbonate are suspended in 4 ml of dimethylformamide and stirredintensively for 20 min. 400 mg of ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy-methyl]acrylate, 25 mg of triphenylphosphine and 212 mg of4-fluoro-3-methyliodo-benzene are added, the mixture is degassed andvented with argon and 10 mg of palladium acetate and 0.2 mol of waterare added. The mixture is heated at 60° C for 4 h. After cooling, 20 mlof ethyl acetate and 50 ml of sat. NaCI solution are added. The organicphase is dried over sodium sulfate, the solvent is removed under reducedpressure and the residue is purified by flash chromatography on silicagel (n-heptane/ethyl acetate=4:1). This gives ethylZ-(1R′,3S′)-3-(4-fluoro-3-methylphenyl)-2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]-acrylate as a colorless oil. C₃₁H₃₈FNO₅ (523.65), MS (ESI): 524(M+H⁺).

[0473] Ethyl2R/S-(4-fluoro-3-methylbenzyl)-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]propionate

[0474] 80 mg of ethylZ-(1R′,3S′)-3-(4-fluoro-3-methylphenyl)-2-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyloxymethyl]acrylateare dissolved in 15 ml of ethyl acetate and, after addition of 30 mg ofPd/C 10%, stirred under 1 bar of H₂ for 24 h. The catalyst is filteredoff and the solvent is evaporated. This gives ethyl2R/S-(4-fluoro-3-methylbenzyl)-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]propionateas a colorless oil. C₃₁H₃₈FNO₅ (521.63), MS (ESI): 522 (M+H⁺).C₃₁H₃₈FNO₅(521.63), MS (ESI): 522 (M+H⁺).

[0475](2R/S)-(4-Fluoro-3-methylbenzyl)-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol4-yl-methoxy)cyclohexyloxy]propionicacid

[0476] 70 mg of ethyl2R/S-(4-fluoro-3-methylbenzyl)-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyloxy]propionateare dissolved in 3 ml of tetrahydro-furan/methanol 3:1, 0.1 ml of 1 NLiOH are added and the mixture is stirred at, room temperature for 18 h.The solvent is removed under reduced pressure and the residue isacidified with trifluoroacetic acid and purified by RP-HPLC. This gives2R/S-(4-fluoro-3-methylbenzyl)-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]propionicacid as a colorless oil. C₂₉H₃₄FNO₅ (495.60), MS (ESI): 496.20 (M+H⁺).

EXAMPLE 10

[0477] rac-3-(cis-5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexanol

[0478] 21.7 g of 1,3-cyclohexanediol and 30.3 g of dibutyltin oxide aredissolved in 450 ml of toluene and, under reflux on a water separator,heated at the boil. During the reaction, the reaction volume is reducedto half its original volume. After 3 hours, the reaction mixture iscooled to room temperature and 300 ml of dimethyl-formamide, 29 g of4-iodomethyl-5-methyl-2-m-tolyloxazole 1 and 23.5 g of cesium fluorideare added. The mixture is stirred at room temperature for 18 hours. Thereaction mixture is diluted by addition of ethyl acetate and washed withsaturated NaCl solution. The organic phase is dried over magnesiumsulfate, the solvent is. removed under reduced pressure and the residueis purified by flash chromatography on silica gel (n-heptane/ethylacetate=10:1→1:4). This gives 58 g ofrac-3-(cis-5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexanol as ayellowish solid which is recrystallized from n-heptane/ethyl acetate.C18H23NO3 (301.39), MS (ESI): 302 (M+H⁺).

[0479] 3-((1R,3S)-cis-5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexanol4

[0480] 25 g ofrac-3-(cis-5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexanol aredissolved in 320 ml of vinyl acetate, and 1.3 g of Chirazyme L-2 Lyo(Boehringer Mannheim) are added. The mixture is stirred at roomtemperature for about three hours (checked by LC-MS for 40-45%conversion) and the enzyme is then filtered off and washed with ethylacetate, and the solvent is removed under reduced pressure. The residueis purified by flash chromatography on silica gel (n-heptane/ ethylacetate=3:1). This gives 8 g of acetate 3 as a colorless oil. C20H25NO4(343.43), MS (ESI): 344 (M+H+). The acetate is taken up in 170 ml ofmethanol and, after addition of 27 ml of 2N NaOH, stirred at roomtemperature for one hour. Most of the solvent is removed under reducedpressure. After addition of in each case 150 ml of water and ethylacetate, the org. phase is washed with NaCl solution. The organic phaseis dried over magnesium sulfate and the solvent is removed under reducedpressure. This gives 6.7 g of3-((1R,3S)-cis-5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexanol as ayellowish solid. C18H23NO3 (301.39), MS (ESI): 302 (M+H+).

[0481]4-((1R,3S)-3-Allyloxycyclohexyloxymethyl)-5-methyl-2-m-tolyloxazole 5

[0482] At room temperature, 470 g of a 60% strength suspension of sodiumhydride are added to a solution of 2.2 g of3-((1R,3S)-cis-5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexanol in 30ml of dimethylformamide, and the mixture is stirred at room temperaturefor 20 minutes. 1.36 ml of allyl bromide are then added. The mixture isstirred at 40° C. until the conversion is complete; if required, furthersodium hydride and allyl bromide are added. After complete conversion(checked by LC-MS), 100 ml of ethyl acetate and 150 ml of sat. NaCIsolution are added. The organic phase is dried over magnesium sulfate,the solvents are removed under reduced pressure and the residue ispurified by flash chromatography on silica gel (n-heptane/ethylacetate=3:1). This gives 2.3 g of4-((1R,3S)-3-allyl-oxycyclohexyloxymethyl)-5-methyl-2-m-tolyloxazole 5as a colorless oil. C21H27NO3 (341.45), MS (ESI): 342 (M+H+).

[0483](1R′,3S′)-3-[3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propane-1,2-diol

[0484] At 0° C., 225 mg of DABCO, 1.4 g of anhydrous N-methylmorpholineN-oxide and 350 pl of osmium tetroxide, 2.5% in tert-butanol, were addedto 2.8 g of4-((1R,3S)-3-allyloxycyclohexyloxymethyl)-5-methyl-2-m-tolyloxazole in 9ml of acetone/water 10:1. After 24 h of stirring at room temperature,2.4 g of sodium metabisulfite were added and, after 10 min, the mixturewas diluted with 25 ml of CH2Cl2. The mixture was filtered and thesolvent was removed under reduced pressure. The residue is purified byflash chromatography on silica gel (n-heptane/ethyl acetate=1:3). Thisgives 2.5 g of2R-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyloxy]propane-1,2-diolas a colorless oil. C₂₁H₂₉NO₅ (375.47), MS (ESI): 376 (M+H⁺).

[0485] 2S-(1S′,3R′)-1-(tert-Butyl dimethylsilanyloxy)-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]propan-2-ol

[0486] At 0° C., 500 mg of imidazole, 1.02 g of tert-butyldimethylsilylchloride and 50 mg of tetrabutylammonium iodide are added to 2.5 g of2R-(1.R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propane-1,2-diolin 30 ml of dichloro-methane. Over a period of 18 h, the mixture isallowed to warm to room temperature and then poured onto ice. Themixture is extracted with dichloro-methane, the extract is dried oversodium sulfate and filtered and the solvent is removed under reducedpressure. The residue is purified by flash chromatography on silica gel(n-heptane/ethyl acetate=2:1→1:2). This gives 2S-(1S′,3R′)-1-(tert-butyldimethylsilanyloxy)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl-oxy]propan-2-ol as a colorless oil. C₂₇H₄₃NO₅Si (489.73), MS (ESI): 490(M+H⁺).

[0487] 2S′-(1S,3R)4-{3-[3-(tert-Butyl dimethylsilanyloxy)-2-prop-2-ynyloxypropoxy]cyclo-hexyloxymethyl}-5-methyl-2-m-tolyloxazole

[0488] 25 mg of a 60% strength sodium hydride suspension are added to245 mg of 2S-(1S′,3R′)-1-(tert-butyl dimethylsilanyloxy)-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]propan-2-olin 3 ml of dimethylformamide, and the mixture is stirred at roomtemperature for 20 min. 200 mg of propargyl bromide are then added, andthe mixture is stirred at room temperature until the conversion iscomplete. The mixture is taken up in sat. NaCI solution/ethyl acetate,the organic phase is dried over sodium sulfate and filtered and thesolvent is removed under reduced pressure. This gives2S′-(1S,3R)-4-{3-[3-(tert-butyl dimethylsilanyloxy)-2-prop-2-ynyloxypropoxy]cyclohexyloxymethyl}-5-methyl-2-m-tolyloxazoleas a colorless oil. C₃₀H₄₅NO₅Si (527.78), MS (ESI): 528 (M+H⁺).

[0489](1R′,3S′)-2R-3-[3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-prop-2-ynyloxy-propan-1-ol

[0490] 2 ml of tetrabutylammonium fluoride, 1M in tetrahydrofuran, areadded to 200 mg of 2S′-(1S,3R)4-{3-[3-(tert-butyl-dimethyl-silanyloxy)-2-prop-2-ynyloxypropoxy]-cyclohexyloxymethyl}-5-methyl-2-m-tolyloxazole in 2 ml oftetrahydrofuran, and the mixture is stirred at room temperature for 2 h.The mixture is taken up in sat. NaCl solution/ethyl acetate, the organicphase is dried over sodium sulfate and filtered and the solvent isremoved under reduced pressure. This gives(1R′,3S′)-2R-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-prop-2-ynyloxypropan-1-olas a colorless oil. C₂₄H₃₁NO₅ (413.53), MS (ESI): 414 (M+H⁺).

[0491] 2 R-(1R′,3S′)-3-[3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-propoxypropan-1-ol

[0492] 50 mg of Pd/C 10% are added to the crude product(1R′,3S′)-2R-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-prop-2-ynyloxypropan-1-ol,dissolved in 20 ml of methanol, and the mixture is stirred under 1 barof hydrogen for 3 h. The catalyst is filtered and the solvent is removedunder reduced pressure. This gives2R-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-propoxypropan-1-ol as a colorless oil. The residue is purified byflash chromatography on silica gel (n-heptane/ethyl acetate =1:1).C₂₄H₃₅NO₅ (417.55), MS (ESI): 418 (M+H⁺).

[0493]2R-(1R′,3S′)-2-(2-Propoxy)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyloxy]propionicacid

[0494] 180 mg of Dess-Martin periodinane are added to 90 mg of2R-(1R′,3S′)-2-propoxy-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-1-olin 1.5 ml of dichloromethane, and the mixture is stirred at roomtemperature for 2 h. 41 mg of Na2S2O₃ in 3 ml of a 5% strength NaHCO₃solution are then added, and the mixture is stirred at room temperaturefor 10 min. The organic phase is separated off, dried over MgSO₄ andconcentrated. The residue is taken up in 2 ml of acetonitrile, and 1.5ml of a 0.65 M NaH2PO₄ solution and 48 μl of 35% strength H₂O₂ solutionare added. At 0° C., 30 mg of NaClO2 in 2 ml of water are added dropwiseover a period of 1 h. The mixture is stirred at this temperature for 3h. Na₂SO₃ solution, 10% HCl and 10 ml of CH₂Cl₂ are then added, thephases are separated and the organic phase is dried over MgSO₄ andconcentrated. Purification of the residue by HPLC gives 1.2 mg of2R-(1R′,3S′)-2-(2-methyl-propoxy)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propionic acid.

EXAMPLE 11

[0495]2R-(1R′,3S′)-3-[3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propanoicacid

[0496] Analogously to Example 10,2S-(1R′,3S′)-1-(tert-butyldimethylsilanyloxy)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 4-trifluoro-methylbenzyl bromide give2R-(1R′,3S′)-3-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid.

EXAMPLE 12

[0497]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]-2-methoxypropionicacid

[0498] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland methyl iodide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-methoxypropionicacid.

EXAMPLE 13

[0499]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoro-methylbenzyloxy)propanoicacid

[0500] Analogously to Example 10, 1-(tert-butyidimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 4-trifluoro- methylbenzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propanoicacid.

EXAMPLE 14

[0501]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(3-trifluoro-methylbenzyloxy)propanoicacid

[0502] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 3-trifluoro-methyl benzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyloxy]-2-(3-trifluoromethylbenzyloxy)propanoicacid.

EXAMPLE 15

[0503]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(3-methoxy-benzyloxy)propanoicacid

[0504] Analogously to Example 10,1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 3-methoxy-benzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclo-hexyloxy]-2-(3-methoxybenzyloxy)propanoicacid.

EXAMPLE 16

[0505]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2,5-dimethylbenzyloxy)propanoicacid

[0506] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 2,5-dimethylbenzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]-2-(2,5-dimethylbenzyloxy)propanoicacid.

EXAMPLE 17

[0507]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-methyl-benzyloxy)propanoicacid

[0508] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 4-methylbenzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]-2-(4-methylbenzyloxy)propanoicacid.

EXAMPLE 18

[0509]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-tert-butylbenzyloxy)propanoicacid

[0510] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 4-tert-butylbenzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyloxy]-2-(4-tert-butylbenzyloxy)propanoicacid.

EXAMPLE 19

[0511]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-trifluoromethylbenzyloxy)propanoicacid

[0512] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 2-trifluoro-methylbenzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyloxy]-2-(2-trifluoromethylbenzyloxy)propanoicacid.

EXAMPLE 20

[0513]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-chlorothien-5-ylmethoxy)propionicacid

[0514] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 2-chlorothien-5-ylmethyl chloride give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)-cyclohexyloxy]-2-(2-chlorothien-5-ylmethoxy)propionicacid.

EXAMPLE 21

[0515]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-butynyl-oxy)propionicacid

[0516] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]propan-2-oland 2-butynyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]-2-(2-butynyloxy)propionic acid.

EXAMPLE 22

[0517]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-propynyl-oxy)propionicacid

[0518] Analogously to Example 10, 1-(tert-butyidimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]propan-2-oland 2-propynyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-propynyloxy)propionic acid.

EXAMPLE 23

[0519]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]-2-(2-pentynyl-oxy)propionicacid

[0520] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 2-pentynyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-pentynyloxy)propionic acid.

EXAMPLE 24

[0521]3-[(1R,3S)-3-(5-Methyl-2-m-tolyl-oxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-propenyl-oxy)propionicacid

[0522] Analogously to Example 10, 1-(tert-butyidimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland allyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-propenyloxy)propionicacid.

EXAMPLE 25

[0523]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(3-phenyl-2-propenyloxy)propionicacid

[0524] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland 3-phenyl-2-propenyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-toly-oxazol-4-ylmethoxy)cyclo-hexyloxy]-2-(3-phenyl-2-propenyloxy)propionicacid.

EXAMPLE 26

[0525]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-methyl-2-propenyloxy)propionicacid

[0526] Analogously to Example 10, 1-(tert-butyldimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland isobutenyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(2-methyl-2-propenoxy)propionic acid.

EXAMPLE 27

[0527]3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-benzyloxy-propionicacid

[0528] Analogously to Example 10, 1-(tert-butyidimethylsilanyloxy)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propan-2-oland benzyl bromide give3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-benzyloxypropionic acid.

EXAMPLE 28

[0529] Benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether

[0530] Under an atmosphere of argon, 12 g of sodium hydride (55-65%) areinitially charged in 200 ml of abs. DMF, and the mixture is stirred atRT for 10 min. With ice-cooling, 54 g of benzyl(1S,3R)-3-hydroxycyclohex-1-yl ether in 70 ml of DMF are added dropwise.The mixture is stirred at RT for 90 min. With ice-cooling, 50 g of allylbromide are slowly added dropwise. After the addition has ended, themixture is stirred at 45° C. for 1 h. According to TLC, the reaction iscomplete. The reaction solution is quenched with 15 ml of iPrOH, dilutedwith water and sat. NaCl solution and extracted with MTBE. The combinedorganic phases are washed with water and NaCI solution, dried over MgSO4and concentrated. This gives 60 g of benzyl(1S,3R)-3-allyloxycyclohex-1-yl ether as a light-beige oil. C16H22O2(246.35), MS (ESI): 247 (M+H⁺).

[0531] (1S,3R)-3-Allyloxycyclohex-1-yl benzoate

[0532] Analogously to benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether,(1S,3R)-3-hydroxycyclohex-1-yl benzoate and allyl bromide give(1S,3R)-3-allyloxycyclohex-1-yl benzoate. C16H20O3 (260.37), MS (ESI):261 (M+H⁺).

[0533] Allyl (1R,3S)-3-trityloxymethylcyclohex-1-yl ether

[0534] Analogously to benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether,(1R,3S)-3-trityloxy-methylcyclohexanol and allyl bromide give allyl(1R,3S)-3-trityloxymethylcyclohex-1-yl ether.

[0535] (2R/2S)-3-[(1S,3R)-3-Benzyloxycyclohexyloxy]propane-1 ,2-diol

[0536] At 0° C., 6.8 g of DABCO, 42.8 g of NMO and 8.0 ml of an osmiumtetroxide solution (2.5% in tert-butanol) are added successively to 60 gof benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether in 200 ml ofacetone/water (10:1). The solution is stirred at RT overnight. After 24h, another 5 ml of osmium tetroxide solution are added, and the solutionis stirred at RT overnight. The reaction is then complete. Sodiumsulfite solution and water are added and the mixture is extracted withdichloromethane. The organic phase is dried over Na2SO4 andconcentrated, giving 65 g of(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]propane-1,2-diol as a brownoil. C16H24O4 (280.37), MS (ESI): 281 (M+H⁺).

[0537] (2R/2S)-3-[(1R,3S)-1-Benzoyloxycyclohex-3-yloxy]propane-1,2-diol

[0538] Analogously to(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]propane-1,2-diol,(1S,3R)-3-hydoxycyclohex-1-yl benzoate, NMO, DABCO and osmium tetroxidegive (2R/2S)-3-[(1R,3S)-1-benzoyloxycyclohex-3-yloxy]propane-1,2-diol.C16H22O5 (294.35), MS (ESI): 295 (M+H⁺).

[0539](2R/2S)-3-[(1R,3S)-3-Trityloxymethylcyclohexyloxy]propane-1,2-diol

[0540] Analogously to(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]propane-1,2-diol, allyl(1R,3S)-3-trityloxymethylcyclohex-1-yl ether, NMO, DABCO and osmiumtetroxide give(2R/2S)-3-[(1R,3S)-3-trityloxymethylcyclohexyloxy]propane-1,2-diol.

[0541] (2R/2S)-3-[(1S,3R)-3-Benzyloxycyclohexyloxy]-2-hydroxypropyltert-butyidiphenyl-silyl ether imidazole

[0542] 20 g of (2 R/2S)-3-[(1S ,3R)-3-benzyloxycyclohexyloxy]propane-1,2-diol are dissolved in 100 ml of DMF, and 12 g of imidazoleand then 20.6 g of TBDPSCI are added and the mixture is stirred at RT.After 3 h, the reaction is complete. Dilution of the solution withwater/sat. NaCl solution, extraction with MTBE and drying of the organicphase over MgSO4 and concentration give 35 g of(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-hydroxypropyltert-butyldiphenylsilyl ether as a yellow oil. C32H42O4Si (518.78), MS(ESI): 519 (M+H⁺).

[0543] (2R/2S)-3-[(1R,3S)-1-Benzoyloxycyclohex-1-yloxy]-2-hydroxypropyltert-butyldi-methylsilyl ether

[0544] Analogously to(2R/2S)-3-[(1S,3R)-3-benzoyloxycyclohex-1-yloxy]-2-hydroxypropyltert-butyldiphenylsilyl ether,(2R/2S)-3-[(1R,3S)-1-benzoyloxycyclohex-3-yloxy ]-propane-1,2-diol,imidazole and TBDMSCI give(2R/2S)-3-[(1S,3R)-1-benzoyloxy-cyclohex-1-yloxy]-2-hydroxypropyltert-butyldimethylsilyl ether. C22H3605Si (408.62), MS (ESI): 409(M+H⁺).

[0545] (2R/2S)-3-[(1R,3S)-3-Trityloxymethylcyclohexyloxy]-2-hydroxypropyl tert-butyidi-phenylsilyl ether

[0546] Analogously to (2 R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-hydroxypropyl tert-butyldiphenylsilylether, (2R/2S)-3-[(1R,3S)-3-trityloxymethylcyclohexyloxy]-propane-1,2-diol, imidazole and TBDPSCI give(2R/2S)-3-[(1R,3S)-3-trityloxy-methylcyclohexyloxy]-2-hydroxypropyltert-butyidiphenylsilyl ether.

[0547] (2R/2S)-3-[(1S,3R)-3-Benzyloxycyclohexyloxy]-2-methoxypropyltert-butyldiphenyl-silyl ether

[0548] 10 g of(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-hydroxypropyltert-butyldi-phenylsilyl ether and 8.5 g of iodomethane are dissolved in100 ml of THF. At RT, 3.3 g of KOtBu are added and the suspension isstirred at RT for 1 h. Sat. NH4Cl solution and water are then added, andthe solution is extracted with MTBE. The combined organic phases aredried over MgSO4 and concentrated. The residue is chromatographed onsilica gel (heptane/ethyl acetate 5:1→1:1), giving 7.2 g of(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-methoxypropyltert-butyldiphenyl-silyl ether as a light-yellow oil.

[0549] (2R/2S)-3-[(1S,3R)-3-Benzyloxycyclohexyloxy]-2-ethoxypropyltert-butyldiphenyl-silyl ether

[0550] Analogously to (2 R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-methoxypropyl tert-butyidiphenylsilylether, (2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-hydroxypropyltert-butyldiphenylsilyl ether and iodoethane give(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-ethoxypropyltert-butyldiphenylsilyl ether.

[0551] (2R/2S)-3-[(1S,3R)-3-Benzyloxycyclohexyloxy]-2-allyloxypropyltert-butyldiphenyl-silyl ether

[0552] Analogously to(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-hydroxypropyltert-butyldiphenylsilyl ether and allyl bromide give(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-allyloxypropyltert-butyIdiphenylsilyl ether.

[0553](2R/2S)-3-[(1S,3R)-3-Benzyloxycyclohexyloxy]-2-(2-methyl-2-propenyloxy)propyltert-butyldiphenylsilyl ether

[0554] Analogously to (2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-methoxypropyl tert-butyldiphenylsilylether, (2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-hydroxypropyltert-butyldiphenylsilyl ether and isobutenyl bromide give(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-(2-methyl-2-propenyloxy)propyltert-butyldi-phenylsilyl ether.

[0555](2R/2S)-3-[(1R,3S)-3-Benzoyloxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)-propyltert-butyidimethylsilyl ether

[0556] Analogously to(2R/2S)-3-[(1S,3R)-3-benzoyloxycyclohex-1-yloxy]-2-(4-trifluoro-methylbenzyloxy)propyltert-butyldimethylsilyl ether,(2R/2S)-3-[(1R,3S)-1-benzoyloxycyclohex-3-yloxy]-2-hydroxypropyltert-butyidiphenylsilyl ether and 4-trifluoromethylbenzyl bromide give(2R/2S)-3-[(1R,3S)-3-benzoyloxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)propyltert-butyidimethylsilyl ether.

[0557](2R/2S)-3-[(1R,3S)-3-Trityloxymethylcyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)-propyltert-butyldiphenylsilyl ether

[0558] Analogously to(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether,(2R/2S)-3-[(1R,3S)-3-trityloxymethylcyclohexyloxy ]-2-hydroxypropyltert-butyidiphenylsilyl ether and 4-trifluoromethylbenzyl bromide give(2R/2S)-3-[(1R,3S)-3-trityloxymethylcyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)-propyltert-butyldiphenylsilyl ether.

[0559] (2R/2S)-3-[(1S,3R)-3-Hydroxycyclohexyloxy]-2-methoxypropyltert-butyldiphenyl-silyl ether

[0560] 7.2 g of(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-methoxypropyltert-butyl-diphenylsilyl ether are dissolved in 40 ml of methanol, 4 gof Pd/C (10%) are added and the mixture is hydrogenated at RT and apressure of 5 bar for 15 h. The catalyst is filtered off, the residue iswashed with dichloromethane and the filtrate is concentrated, giving 6.0g of (2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether as a colorless oil. C26H38O4Si (442.68),MS (ESI): 443 (M+H⁺).

[0561] (2R/2S)-3-[(1S,3R)-3-Hydroxycyclohexyloxy]-2-ethoxypropyltert-butyldiphenylsilyl ether

[0562] Analogously to(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-ethoxy-propyltert-butyldiphenylsilyl ether gives(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyl-oxy]-2-ethoxypropyltert-butyldiphenylsilyl ether. C27H40O4Si (456,70), MS (ESI): 457(M+H⁺).

[0563](2R/2S)-3-[(1R,3S)-3-Hydroxymethylcyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)-propyltert-butyldiphenylsilyl ether

[0564] 3.5 g of(2R/2S)-3-[(1R,3S)-3-trityloxymethylcyclohexyloxy]-2-(4-trifluoromethyl-benzyloxy)propyl tert-butyldiphenylsilyl ether are dissolved in 100 ml of MTBE, 58g of formic acid are added and the mixture is stirred at RT. Thesolution is concentrated and the residue is chromatographed on silicagel, giving 170 mg of(2R/2S)-3-[(1R,3S)-3-hydroxymethylcyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)-propyltert-butyldiphenylsilyl ether as a colorless oil.

[0565] (2R/2S)-3-[(1S ,3R)-3-Hydroxycyclohexyloxy]-2-propoxypropyltert-butyldiphenyl-silyl ether

[0566] Analogously to(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-propoxy-propyltert-butyldiphenylsilyl ether gives(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyl-oxy]-2-propoxypropyltert-butyldiphenylsilyl ether. C28H42O4Si (470.73), MS (ESI): 471(M+H⁺).

[0567] (2R/2S)-3-[(1S,3R)-3-Hydroxycyclohexyloxy]-2-isobutoxypropyltert-butyldiphenyl-silyl ether

[0568] Analogously to(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy]-2-iso-butoxypropyltert-butyldiphenylsilyl ether gives(2R/2S)-3-[(1S,3R)-3-hydroxycyclo-hexyloxy]-2-isobutoxypropyltert-butyldiphenylsilyl ether. C29H44O4Si (484.76), MS (ESI): 485(M+H⁺).

[0569](2R/2S)-3-[(1R,3S)-1-Hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether

[0570] 4.6 g of(2R/2S)-3-[(1S,3R)-1-benzoyloxycyclohex-3-yloxy]-2-(4-trifluoromethoxy-benzyloxy)tert-butyldimethylsilyl ether are dissolved in 20 ml of methanol, 2.2 gof K2CO3 are added and the mixture is stirred at RT for 72 h. The K2CO3is filtered off, the residue is washed with methanol and the filtrate isconcentrated, giving 0.85 g of (2R/2S)-3-[(1R,3S)-3-hydroxycyclohexyloxy]-2-(4-trifluoromethylbenzyl-oxy) tert-butyldimethylsilyl ether as acolorless oil. C23H37F3O4Si (462.63), MS (ESI): 463 (M+H⁺).

[0571]2-Methoxy-3-[(1R,3S)-3-(5-methyl-2-phenyloxazol-4-ylmethoxy)cyclohexyloxy]-propanoicacid

[0572] 100 mg of(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyltert-butyl-diphenylsilyl ether are dissolved in 2 ml of THF, and 83 mgof 2-phenyl-5-methyloxazol-4-ylmethyl chloride and 51 mg of KOtBu areadded successively. The reaction mixture is shaken at RT overnight. 214mg of TBAF are added, and the suspension is allowed to stand overnight.Water and MBTE are added and the organic phase is then separated off andconcentrated. The residue is taken up in acetone, and 1 ml of 1.92 MJones reagent are added. The reaction solution is shaken overnight. Thesolution is diluted with 3 ml of water and poured onto an extractioncartridge (kieselguhr, for 20 ml of aqueous phases). The cartridge isthen eluted with ethyl acetate and the resulting solution isconcentrated and purified by HPLC. This gives 5 mg of2-methoxy-3-[(1R,3S)-3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)cyclohexyloxy]propionicacid as a yellow oil.

EXAMPLE 29

[0573]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionicacid

[0574] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(3-trifluoromethyl-phenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(3-tri-fluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 30

[0575]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethoxyphenyl)oxazol4-yl-methoxy]cyclohexyloxy}propionicacid

[0576] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyidiphenylsilyl ether and5-methyl-2-(3-trifluoromethoxy-phenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethoxyphenyl)oxazol4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 31

[0577]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionic acid

[0578] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-trifluoromethyl-phenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(4-tri-fluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 32

[0579]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}propionicacid

[0580] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(4-methylphenyl)-oxazol-4-ylmethoxy]cyclohexyloxy}propionic acid

EXMPLE 33

[0581]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(2,6-dimethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionicacid

[0582] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(2,6-dimethylphenyl)-oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(2,6-dimethyl-phenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 34

[0583]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionicacid

[0584] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyl tert-butyldiphenylsilyl ether and5-methyl-2-(2-trifluoromethyl-phenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(2-tri-fluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 35

[0585]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(3-naphthyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}propionicacid

[0586] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-methoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(2-naphthyl)oxazol-4-yl-methyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(3-naphthyl)oxazol-4-yl-methoxy]cyclohexyloxy}propionicacid.

EXAMPLE 36

[0587]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(2,4-dimethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionicacid

[0588] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyl tert-butyldiphenylsilyl ether and 5-methyl-2-(2 ,4-dimethylphenyl)-oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(2,4-dimethyl-phenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionic acid.

EXAMPLE 37

[0589]2-Methoxy-3-{(1R,3S)-3-[5-methyl-2-(4-biphenyl)oxazol-4-ylmethoxy]-cyclohexyl-oxy}propionicacid

[0590] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-biphenyl)oxazol-4-yl-methyl iodide give2-methoxy-3-{(1R,3S)-3-[5-methyl-2-(4-biphenyl)oxazol4-yl-methoxy]cyclohexyloxy}propionicacid.

EXAMPLE 38

[0591]2-Methoxy-3-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol4-ylmethoxy]-cyclo-hexyloxy}propionicacid

[0592] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)-oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 39

[0593]2-Methoxy-3-{(1R,3S)-3-[5-ethyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}propionicacid

[0594] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(4-methylphenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-ethyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 40

[0595]2-Methoxy-3-{(1R,3S)-3-[5-ethyl-2-(2-trifluoromethylphenyl)oxazol4-ylmethoxy]-cyclohexyloxy}propionic acid

[0596] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(2-trifluoromethylphenyl)-oxazol 4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-ethyl-2-(2-trifluoromethyl-phenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionic acid.

EXAMPLE 41

[0597]2-Methoxy-3-{(1R,3S)-3-[5-ethyl-2-(2,6-dimethylphenyl)oxazol4-ylmethoxy]cyclo-hexyloxy}propionicacid

[0598] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-methoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(2,6-methylphenyl)oxazol-4-ylmethyl iodide give2-methoxy-3-{(1R,3S)-3-[5-ethyl-2-(2,6-dimethylphenyl)-oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 42

[0599] 3-[(1R,3S)-3-(5-Methyl-2-phenyloxazol-4-ylmethoxy)cyclohexyloxy]-2-propoxy-propionic acid

[0600] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and 5-methyl-2-phenyloxazol-4-ylmethyliodide give3-[(1R,3S)-3-(5-methyl-2-phenyloxazol-4-ylmethoxy)cyclohexyloxy]-2-propoxypropionic acid.

EXAMPLE 43

[0601]3-[(1R,3S)-3-(5-Methyl-2-(3-tolyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-propoxy-propionicacid

[0602] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-propoxypropyltert-butyldiphenylsilyl ether and 5-methyl-2-(3-tolyl)oxazol-4-yl-methyliodide give3-[(1R,3S)-3-(5-methyl-2-(3-tolyl)oxazol-4-ylmethoxy)cyclo-hexyloxy]-2-propoxypropionicacid.

EXAMPLE 44

[0603]3-{(1R,3S)-3-[5-Methyl-2-(3-trifluoromethoxyphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}-2-propoxypropionicacid

[0604] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-propoxypropyltert-butyidiphenylsilyl ether and2-(3-trifluoromethoxyphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionic acid.

EXAMPLE 45

[0605]3-{(1R,3S)-3-[5-Methyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid

[0606] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-propoxypropyltert-butyidiphenylsilyl ether and 2-(3-methoxyphenyl)oxazol-4-ylmethyliodide give3-{(1R,3S)-3-[5-methyl-2-(3-methoxyphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 46

[0607]3-{(1R,3S)-3-[5-Methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}-2-propoxypropionicacid

[0608] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyidiphenylsilyl ether and2-(4-trifluoromethylphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 47

[0609]3-{(1R,3S)-3-[5-Methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid

[0610] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and 2-(4-methylphenyl)oxazol-4-yl-methyliodide give 3-{(1R,3S)-3-[5-methyl-2-(4-methylphenyl)oxazol4-ylmethoxy]-cyclohexyloxy}-2-propoxypropionic acid.

EXAMPLE 48

[0611]3-{(1R,3S)-3-[5-Methyl-2-(4-trifluoromethoxyphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}-2-propoxypropionic acid

[0612] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyidiphenylsilyl ether and2-(4-trifluoromethoxyphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-methyl-2-(4-trifluoromethoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 49

[0613]3-{(1R,3S)-3-[5-Methyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionic acid

[0614] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyidiphenylsilyl ether and2-(4-isopropylphenyl)oxazol-4-yl-methyl iodide give3-{(1R,3S)-3-[5-methyl-2-(4-isopropylphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 50

[0615]3-{(1R,3S)-3-[5-Methyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}-2-propoxypropionic acid

[0616] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and2-(2-trifluoromethylphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-methyl-2-(2-trifluoromethylphenyl)oxazol4-yl-methoxy]cyclohexyloxy}-2-propoxypropionic acid.

EXAMPLE 51

[0617]3-{(1R,3S)-3-[5-Methyl-2-(2-naphthylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionic acid

[0618] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and 2-(2-naphthyl)oxazol-4-ylmethyl iodidegive 3-{(1R,3S)-3-[5-methyl-2-(2-naphthylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}-2-propoxypropionic acid.

EXAMPLE 52

[0619]3-{(1R,3S)-3-[5-Methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}-2-propoxypropionic acid

[0620] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and2-(3-trifluoromethylphenyl)oxazol4-ylmethyl iodide give3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol4-yl-methoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 53

[0621]3-{(1R,3S)-3-[5-Ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid

[0622] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyidiphenylsilyl ether and5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 54

[0623]3-{(1R,3S)-3-[5-Ethyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionic acid

[0624] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyidiphenylsilyl ether and5-ethyl-2-(4-methylphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-ethyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 55

[0625]3-{(1R,3S)-3-[5-Ethyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}-2-propoxypropionicacid

[0626] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(2-trifluoromethylphenyl)-oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-ethyl-2-(2-trifluoromethylphenyl)-oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 56

[0627]3-{(1R,3S)-3-[5-Ethyl-2-(2,6-dimethylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionic acid

[0628] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(2,6-dimethylphenyl)-oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-ethyl-2-(2,6-dimethylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 57

[0629]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionic acid

[0630] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(3-trifluoromethylphenyl)-oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-trifluoro-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 58

[0631]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethoxyphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionicacid

[0632] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyidiphenylsilyl ether and5-methyl-2-(3-trifluoromethoxy-phenyl)oxazol4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-tri-fluoromethoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 59

[0633]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionicacid

[0634] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-trifluoro-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 60

[0635]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-trifluoromethoxyphenyl)oxazol-4-ylmethoxy]-cyclohexyloxy}propionic acid

[0636] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyidiphenylsilyl ether and5-methyl-2-(4-trifluoromethoxy-phenyl)oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-tri-fluoromethoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 61

[0637]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}propionic acid

[0638] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-isopropylphenyl)-oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-isopropyl-phenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 62

[0639]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(2-trifluoromethylphenyl)oxazol4-ylmethoxy]-cyclohexyloxy}propionic acid

[0640] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(2-trifluoromethylphenyl)-oxazol4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(2-trifluoro-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionic acid.

EXAMPLE 63

[0641]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(2,4-dimethylphenyl)oxazol4-ylmethoxy]cyclo-hexyloxy}propionicacid

[0642] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(2,4-dimethylphenyl)-oxazol4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(2,4-dimethyl-phenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 64

[0643]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-biphenyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}propionicacid

[0644] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-biphenyl)oxazol-4-yl-methyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-biphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}propionicacid.

EXAMPLE 65

[0645]2-Ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(2-tolyl)oxazol-4-ylmethoxy)cyclohexyloxy]-propionicacid

[0646] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl iodide give2-ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(2-tolyl)oxazol-4-ylmethoxy)-cyclohexyloxy]propionicacid.

EXAMPLE 68

[0647]2-Ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy)cyclo-hexyloxy]propionicacid

[0648] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(4-isopropylphenyl)-oxazol-4-ylmethyl iodide give2-ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(4-isopropyl-phenyl)oxazol-4-ylmethoxy)cyclohexyloxy]propionicacid.

EXAMPLE 67

[0649]2-Ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(2-trifluoromethylphenyl)oxazol-4-ylmethoxy)-cyclohexyloxy]propionicacid

[0650] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(2-trifluoromethylphenyl)-oxazol-4-ylmethyl iodide give2-ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(2-trifluoromethyl-phenyl)oxazol-4-ylmethoxy)cyclohexyloxy]propionicacid.

EXAMPLE 68

[0651]2-Ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(2,4-dimethylphenyl)oxazol4-ylmethoxy)cyclo-hexyloxy]propionicacid

[0652] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(2,4-dimethylphenyl)-oxazol-4-ylmethyl iodide give2-ethoxy-3-[(1R,3S)-3-(5-ethyl-2-(2,4-dimethyl-phenyl)oxazol-4-ylmethoxy)cyclohexyloxy]propionicacid.

EXAMPLE 68

[0653]3-{(1R,3S)-3-[5-Ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid

[0654] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(4-isopropylphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-ethyl-2-(4-isopropylphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-propoxypropionic acid.

EXAMPLE 70

[0655]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-phenyloxazol-4-ylmethoxy]cyclohexyloxy}-propionicacid

[0656] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and 5-methyl-2-phenyloxazol-4-ylmethyliodide give 2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-phenyloxazol-4-ylmethoxy]cyclo-hexyloxy}propionic acid.

EXAMPLE 71

[0657]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-methylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}propionic acid

[0658] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(3-methylphenyl)oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 72

[0659]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}propionicacid

[0660] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyldiphenylsilyl ether and5-methyl-2-(3-methoxyphenyl)oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(3-methoxyphenyl)-oxazol4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 73

[0661]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}propionicacid

[0662] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyidiphenylsilyl ether and5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}propionicacid.

EXAMPLE 74

[0663]2-Ethoxy-3-{(1R,3S)-3-[5-methyl-2-(2-naphthyl)oxazol-4-ylmethoxy]cyclohexyloxy}-propionicacid

[0664] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-benzyloxycyclohexyloxy ]-2-ethoxypropyltert-butyidiphenylsilyl ether and5-methyl-2-(2-naphthyl)oxazol-4-yl-methyl iodide give2-ethoxy-3-{(1R,3S)-3-[5-methyl-2-(2-naphthyl)oxazol-4-yl-methoxy]cyclohexyloxy}propionicacid.

EXAMPLE 75

[0665]3-{(1R,3S)-3-[5-Ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-propoxypropionicacid

[0666] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-propoxypropyltert-butyldiphenylsilyl ether and5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-propoxypropionicacid.

EXAMPLE 76

[0667](R)-3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxy]-2-(4-tri-fluoromethylbenzyloxy)propionicacid

[0668] By separating3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propanoic acid (Example 13) by chiralHPLC, in addition to enantiomerically pure(S)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid (Example 10),(R)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl-oxy]-2-(4-trifluoromethylbenzyloxy)propionic acid is obtained.

EXAMPLE 77

[0669] (R)-3-[(1R,3S)-3-(5-Methyl-2-(3-trifluoromethylphenyl )oxazol4-ylmethoxy)cyclo-hexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid

[0670] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether and5-methyl-2-(3-trifluoro-methylphenyl)oxazol4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(3-tri-fluoromethylphenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyl-oxy)propionic acid.

EXAMPLE 78

[0671](R)-3-[(1R,3S)-3-(5-Methyl-2-(4-trifluoromethoxyphenyl)oxazol4-ylmethoxy)cyclo-hexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0672] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether and5-methyl-2-(3-trifluoro-methoxyphenyl)oxazol-4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(4-tri-fluoromethoxyphenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethyl-benzyloxy)propionicacid.

EXAMPLE 79

[0673](R)-3-[(1R,3S)-3-(5-Methyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy)cyclohexyl-oxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0674] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether and5-methyl-2-(4-isopropyl-phenyl)oxazol-4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(4-isopropyl-phenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid.

EXAMPLE 80

[0675](R)-3-[(1R,3S)-3-(5-Methyl-2-(2-naphthyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0676] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether and5-methyl-2-(2-naphthyl)-oxazol-4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(2-naphthyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid.

EXAMPLE 81

[0677](R)-3-[(1R,3S)-3-(5-Methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0678] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyidimethylsilyl ether and5-methyl-2-(4-methyl-phenyl)oxazol-4-yl methyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(4-methyl-phenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid.

EXAMPLE 82

[0679](R)-3-[(1R,3S)-3-(5-Methyl-2-(4-trifluoromethoxyphenyl)oxazol-4-ylmethoxy)cyclo-hexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0680] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether and5-methyl-2-(4-trifluoro-methoxyphenyl)oxazol4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(4-tri-fluoromethoxyphenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethyl-benzyloxy)propionic acid.

EXAMPLE 83

[0681](R)-3-[(1R,3S)-3-(5-Methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy)cyclo-hexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0682] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyldimethylsilyl ether and5-methyl-2-(3-trifluoro-methylphenyl)oxazol4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(3-tri-fluoromethylphenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyl-oxy)propionic acid.

EXAMPLE 84

[0683](R)-3-[(1R,3S)-3-(5-Methyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy)cyclohexyl-oxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0684] Analogously to Example 28,(2R/2S)-3-[(1R,3S)-1-hydroxycyclohex-1-yloxy]-2-(4-trifluoromethylbenzyloxy)tert-butyidimethylsilyl ether and5-methyl-2-(3-methoxy-phenyl)oxazol-4-ylmethyl iodide give(R)-3-[(1R,3S)-3-(5-methyl-2-(3-methoxy-phenyl)oxazol-4-ylmethoxy)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid.

EXAMPLE 85

[0685]3-{(1R,3S)-3-[5-Methyl-2-(3-trifluoromethylphenyl)oxazol-4-ylmethoxy]cyclohexyl-oxy}-2-isobutoxypropionicacid

[0686] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-iso-butoxypropyltert-butyidiphenylsilyl ether and2-(3-trifluoromethylphenyl)oxazol-4-ylmethyl iodide give3-{(1R,3S)-3-[5-methyl-2-(3-trifluoromethylphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-isobutoxypropionic acid.

EXAMPLE 86

[0687]3-{(1R,3S)-3-[5-Methyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-isobutoxypropionicacid

[0688] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-iso-butoxypropyltert-butyidiphenylsilyl ether and 2-(3-methoxyphenyl)oxazol-4-yl-methyliodide give3-{(1R,3S)-3-[5-methyl-2-(3-methoxyphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-isobutoxypropionic acid.

EXAMPLE 87

[0689]3-{(1R,3S)-3-[5-Methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-isobutoxypropionicacid

[0690] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy ]-2-iso-butoxypropyltert-butyldiphenylsilyl ether and 2-(4-methylphenyl)oxazol-4-ylmethyliodide give 3-{(1R,3S)-3-[5-methyl-2-(4-methylphenyl)oxazol-4-ylmethoxy]cyclo-hexyloxy}-2-isobutoxypropionic acid.

EXAMPLE 88

[0691]3-{(1R,3S)-3-[5-Methyl-2-(4-isopropylphenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-2-isobutoxypropionicacid

[0692] Analogously to Example 28,(2R/2S)-3-[(1S,3R)-3-hydroxycyclohexyloxy]-2-iso-butoxypropyltert-butyldiphenylsilyl ether and2-(4-isopropylphenyl)oxazol-4-yl-methyl iodide give3-{(1R,3S)-3-[5-methyl-2-(4-isopropylphenyl)oxazol-4-yl-methoxy]cyclohexyloxy}-2-isobutoxypropionicacid.

EXAMPLE 89

[0693](2R/2S)-3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0694] 333 mg of(2R/2S)-3-[(1R,3S)-3-hydroxymethylcyclohexyloxy]-2-(4-trifluoro-methylbenzyloxy)propyltert-butyldiphenylsilyl ether are dissolved in MTBE, 125 mg of potassiumtert-butoxide and 347 mg of 5-methyl-2-(3-methylphenyl)-oxazol4-ylmethyl iodide are added successively and the mixture is stirred atRT. After the reaction has gone to completion, water and MTBE are addedand the organic phase is separated off, dried over MgSO4 andconcentrated. The residue is chromatographed on silica gel(Flash-Master, heptane/ethyl acetate 1:0→1:1→0:1). Theproduct-containing fractions are concentrated, the residue (420 mg) isdissolved in 10 ml of THF and 174 mg of TBAF are added. After 72 h ofstirring, water and MTBE are added and the organic phase is separatedoff, washed with NaCI solution, dried over MgSO4 and concentrated. Theresidue is dissolved in 2 ml of acetone, 0.5 ml of 1.9M Jones reagent isadded and the mixture is stirred at RT overnight. After addition ofwater and MTBE, the organic phase is separated off, dried over MgSO4 andconcentrated. The residue is purified by HPLC, giving 200 mg of(2R/2S)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)-cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid. C30H34F3NO6 (561.6), MS(ESI): 562 (M+H+).

[0695](S)-3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol4-ylmethoxymethyl)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0696] Separation of(2R/2S)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)-cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid by chiral HPLC gives(2S)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol4-ylmethoxymethyl)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid. C30H34F3NO6 (561.6), MS(ESI): 562 (M+H+).

EXAMPLE 90

[0697](R)-3-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionicacid

[0698] Separation of(2R/2S)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)-cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid by chiral HPLC gives(2R)-3-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyloxy]-2-(4-trifluoromethylbenzyloxy)propionic acid. C30H34F3NO6 (561.6), MS(ESI): 562 (M+H+).

EXAMPLE 91

[0699]2-[(1R,3S)-3-(5-Methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]-3-(3-trifluoromethylphenyl)propionicacid

[0700] Analogously to Example 9, ethyl(1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyloxymethyl]acrylate and 3-bromobenzotrifluoride give2-[(1R,3S)-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]-3-(3-trifluoromethylphenyl)propionicacid.

[0701] Characterization of the examples by mass spectroscopy: Found byMS Mass of the (ESI) as Example Empirical formula monoisotope (M + H⁺) 1C23H30FNO5 419.49 420 2 C24H32FNO5 433.52 434 3 C21H26FNO5 391.44 392 4C22H28FNO5 405.47 406 5 C23H29NO5 399.49 400 6 C31H40N2O5 520.67 521 7C30H38N2O5 506.65 507 8 C23H31NO6 417.51 418 9 C29H34FNO5 495.60 496 10C24H33NO6 431.53 432 11 C29H32F3NO6 547.58 548 12 C22H29NO6 403.48 40413 C29H32F3NO6 547.58 548 14 C29H32F3NO6 547.58 548 15 C29H35NO7 509.61510 16 C30H37NO6 507.63 508 17 C29H35NO6 493.61 494 18 C32H41NO6 535.69536 19 C29H32F3NO6 547.58 548 20 C26H30CINO6S 520.05 521 21 C25H31NO6441.53 442 22 C24H29NO6 427.50 428 23 C26H33NO6 455.56 456 24 C24H31NO6429.52 430 25 C30H35NO6 505.62 506 26 C25H33NO6 443.55 444 27 C28H33NO6479.58 480 28 C21H27NO6 389.45 390 29 C22H26F3NO6 457.45 458 30C22H26F3NO7 473.45 474 31 C22H26F3NO6 457.45 458 32 C22H29NO6 403.48 40433 C23H31NO6 417.51 418 34 C22H26F3NO6 457.45 458 35 C25H29NO6 439.51440 36 C23H31NO6 417.51 418 37 C27H31NO6 465.55 466 38 C23H31NO7 433.51434 39 C23H31NO6 417.51 418 40 C23H28F3NO6 471.48 472 41 C24H33NO6431.53 432 42 C23H31NO6 417.51 418 43 C24H33NO6 431.53 432 44C24H30F3NO7 501.50 502 45 C24H33NO7 447.53 448 46 C24H30F3NO6 485.51 48647 C24H33NO6 431.53 432 48 C24H30F3NO7 501.50 502 49 C26H37NO6 459.59460 50 C24H30F3NO6 485.51 486 51 C27H33NO6 467.57 468 52 C24H30F3NO6485.51 486 53 C25H35NO7 461.56 462 54 C25H35NO6 445.56 446 55C25H32F3NO6 499.53 500 56 C26H37NO6 459.59 460 57 C23H28F3NO6 471.48 47258 C23H28F3NO7 487.48 488 59 C23H28F3NO6 471.48 472 60 C23H28F3NO7487.48 488 61 C25H35NO6 445.56 446 62 C23H28F3NO6 471.48 472 63C24H33NO6 431.53 432 64 C28H33NO6 479.58 480 65 C24H33NO6 431.53 432 66C26H37NO6 459.59 460 67 C24H30F3NO6 485.51 486 68 C25H35NO6 445.56 44669 C27H39NO6 473.62 474 70 C22H29NO6 403.48 404 71 C23H31NO6 417.51 41872 C23H31NO7 433.51 434 73 C23H31NO6 417.51 418 74 C26H31NO6 453.54 45475 C24H33NO7 447.53 448 76 C29H32F3NO6 547.58 548 77 C29H29F6NO6 601.55602 78 C29H29F6NO7 617.55 618 79 C31H36F3NO6 575.63 576 80 C32H32F3NO6583.61 584 81 C29H32F3NO6 547.58 548 82 C29H29F6NO7 617.55 618 83C29H29F6NO6 601.55 602 84 C29H32F3NO7 563.58 564 85 C25H32F3NO6 499.53500 86 C25H35NO7 461.56 462 87 C25H35NO6 445.56 446 88 C27H39NO6 473.62474 89 C30H34F3NO6 561.60 562 90 C30H34F3NO6 561.60 562 91 C29H32F3NO5531.58 532

[0702]

1 2 1 19 DNA Artificial Binding Site of Yeast Transcription Factor GAL41 cggagtactg tcctccgag 19 2 19 DNA Artificial Binding Site of YeastTranscription Factor GAL4 2 ctcggaggac agtactccg 19

We claim:
 1. A compound of the formula I

wherein: Ring A is (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl,wherein one or more carbon atoms of said (C3-C8)-cycloalkanediyl and(C3-C8)-cycloalkenediyl groups are optionally replaced by oxygen atoms;R1, R2 are each independently H, F, Cl, Br, CF₃, OCF₃, (C1-C6)-alkyl,O-(C1-C6)-alkyl, SCF₃, SF₅, OCF₂-CHF₂, (C6-C10)-aryl, (C6-C10)-aryloxy,OH or NO₂; or R1 and R2, taken together with the atoms of the phenyl,pyridine, 1-H-pyrrole, thiophene or furan rings to which they areattached, form a fused, partially saturated or unsaturated, bicyclic(C6-C10)-aryl or (C5-C11)-heteroaryl group; R3 is H, (C1-C6)-alkyl,(C3-C8)-cycloalkyl, (C1-C3)-alkyl-(C3-C8)-cycloalkyl, phenyl,(C1-C3)-alkyl-phenyl, (C5-C6)-heteroaryl,(C1-C3)-alkyl-(C5-C6)-heteroaryl or (C1-C3)-alkyl which is fully orpartially substituted by F; W is CH or N, if o=1; W is O,S or NR9,ifo=0; X is (C1-C6)-alkanediyl, wherein one or more carbon atoms of said(C1-C6)-alkanediyl group are optionally replaced by oxygen atoms; Y1 isO; Y2 is CR12R13, SO or SO₂; n is 0,1 or 2; R4 is H, F or (C1-C6)-alkyl;R5 is H, F or (C1-C6)-alkyl; R6 is H or (C1-C6)-alkyl; or is F if n isnot 0; R7 is H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,(C3-C8)-cycloalkyl, phenyl, (C5-C11)-heteroaryl, O-(C3-C8)-cycloalkyl orO-phenyl, wherein said (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl,O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl and 0-phenyl groups are optionally substituted byOH, NR10R11, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl,O-(C3-C8)-cycloalkyl, 0-phenyl or O-(C5-C11)-heteroaryl, and said(C3-C8)-cycloalkyl, phenyl and (C5-C11)-heteroaryl groups are optionallysubstituted by OH, NR10OR11, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl,O-(C2-C6)-alkynyl, O-(C3-C8)-cycloalkyl, O-phenyl, O-(C5-C11)-heteroarylor (C1-C6)-alkyl, wherein said (C1-C6)-alkyl substituent is optionallysubstituted by F (fully or partially) or O-(C1-C6)-alkyl, wherein saidO-(C1-C6)-alkyl substituent is optionally substituted by F (fully orpartially), Cl, Br, I, OH, NR10R11, CO-(C1-C6)-alkyl, CO-(C6-C10)-aryl,CO-(C1-C6)-alkyl-(C6-C10)-aryl, CO-(C5-C11 )-heteroaryl,C(O)-O-(C1-C6)-alkyl, C(O)-O-(C1-C6)-alkyl-(C6-C10)-aryl, C(O)-O-(C6-C10)-aryl, C(O)-O-(C5-C11)-heteroaryl, SO₂-(C1-C6)-alkyl,SO₂-(C1-C6)-alkyl-(C6-C10)-aryl, SO₂-(C1-C6)-alkyl-SO₂-(C1-C6)-alkyl,SO₂-(C6-C10)-aryl, SO₂-(C5-C11)-heteroaryl; or R6 and R7, together withthe carbon atom to which they are attached, form a (C3-C8)-cycloalkylgroup; R8 is H or (C1-C6)-alkyl; R9 is H or (C1-C6)-alkyl which isoptionally substituted by phenyl; R10 is H or (C1-C6)-alkyl which isoptionally substituted by phenyl; R11 is H or (C1-C6)-alkyl which isoptionally substituted by phenyl; R12 is H or (C1-C6)-alkyl; R13 is H or(C1-C6)-alkyl; and pharmaceutically acceptable salts thereof.
 2. Thecompound of claim 1 wherein: Ring A is (C₃-C₈)-cycloalkanediyl or(C₃-C₈)-cycloalkenediyl, wherein one or more of the carbon atoms in said(C₃-C₈)-cycloalkanediyl or (C₃-C₈)-cycloalkenediyl groups are optionallyreplaced by oxygen atoms; X is (C1-C6)-alkanediyl, wherein the C1 or C2carbon atom (with respect to Ring A) in said (C1-C6)-alkanediyl group isoptionally replaced by an oxygen atom; and pharmaceutically acceptablesalts thereof.
 3. The compound of claim 2 wherein: Ring A iscis-cyclohexane-1,3-diyl; R1, R2 are each independently H, F, CF3,(C1-C6)-alkyl, O-(C1-C6)-alkyl or phenyl, or R1 and R2, taken togetherwith the atoms of the phenyl ring to which they are attached, formnaphthyl; R3 is (C1-C6)-alkyl; W is CH,if o=1; X is (CH2)O or CH2-O-CH2;Y1 is 0; Y2 is CH2; n is0 or 1; R4 is H; R5 is H; R6 is H; R7 is H,(C1-C6)-alkyl, O-(C1-C6)-alkyl, (C1-C6)-alkyl-O-(C1-C6)-alkyl,(C2-C6)-alkenyl, O-(C2-C6)-alkenyl, O-(C2-C6)-alkynyl or CH2NR10R11,wherein said (C1-C6)-alkyl, O-(C1-C6)-alkyl, (C2-C6)-alkenyl andO-(C2-C6)-alkenyl groups are optionally substituted by phenyl or(C5-C6)-heteroaryl, wherein said phenyl and (C5-C6)-heteroaryl groupsare optionally substituted by (C1-C6)-alkyl, O-(C1-C6)-alkyl or CF3; orR6 and R7, taken together with the carbon atom to which they areattached, form (C3-C6)-cycloalkyl; R8 is H; R10 is (C1-C6)-alkyl; R11 is(C1-C6)-alkyl substituted by phenyl; and pharmaceutically acceptablesalt thereof.
 4. A pharmaceutical composition comprising apharmaceutically acceptable carrier and one or more compounds ofclaim
 1. 5. The pharmaceutical composition of claim 4 further comprisingat least one additional active ingredient.
 6. The pharmaceuticalcomposition of claim 5 wherein said additional active ingredient hasfavorable effects on metabolic disturbances or disorders.
 7. Thepharmaceutical composition of claim 5 wherein said additional activeingredient is an antidiabetic.
 8. The pharmaceutical composition ofclaim 5 wherein said additional active ingredient is a lipid modulator.9. A method of treating disorders of fatty acid metabolism and glucoseutilization comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim
 1. 10. A methodof treating disorders of insulin resistence comprising administering toa patient in need thereof a therapeutically effective amount of acompound of claim
 1. 11. A method of treating diabetes mellitusincluding the prevention of the squelae associated therewith comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim
 1. 12. A method of treating dyslipidemiaand squelae associated therewith comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim
 1. 13. A method of treating metabolic syndrome and conditionsassociated therewith comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 14.A method of treating disorders of fatty acid metabolism and glucoseutilization comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1 in combinationwith at least one further active compound.
 15. A method of treatingdisorders of insulin resistance comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of claim 1in combination with at least one further active compound.